3rd Generation TKI Research Articles

EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis.

We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2-13.4 months) and PFS was 3.2 months (95% CI 2.5-3.9 months). ORR was 15% (95% CI 10-21%) and DCR was 61% (95% CI 53-67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited.

YL202/BNT326, a HER3-targeted ADC, in patients with locally advanced or metastatic non-small cell lung cancer and breast cancer: Preliminary results from a first-in-human phase I trial.

3034 Background: YL202/BNT326 is a novel ADC consisting of an anti-HER3 IgG1 monoclonal antibody linked to 8 molecules of YL0010014, a novel topoisomerase I inhibitor, via a tripeptide linker. We report preliminary safety and efficacy results from a phase I trial of YL202/BNT326. Methods: This multinational trial is recruiting patients (pts) with locally advanced/metastatic non-small cell lung cancer (NSCLC) with an EGFR-activating mutation who were previously treated with 3rd generation TKI and platinum-based chemotherapy, and pts with unresectable, locally advanced or metastatic, HR-positive and HER2-negative (IHC 0,1+,2+/ISH-) breast cancer (BC) who were previously treated with CDK4/6 inhibitor and at least one line of chemotherapy. YL202/BNT326 was given at 6 dose levels (DLs, Q3W, iv) in a BOIN dose escalation (D-ESC) scheme, followed by cohort backfill(BF) at selected doses. Primary endpoints are safety and tolerability (dose-limiting toxicities [DLTs] and adverse events [AEs]). Secondary endpoints include pharmacokinetics [PK] and efficacy per RECIST v1.1(ORR, DCR, BOR). Results: At data cutoff (4 Feb 2024), 52 pts were enrolled in D-ESC and BF (39 NSCLC, 13 BC). One DLT (grade 3 febrile neutropenia) occurred during D-ESC at the highest dose. Most common TRAEs (>20%, all grade / ≥ G3) were anemia (71%/20%), white blood cell count decreased (67%/31%), neutrophil count decreased (63%/29%), nausea (52%/0%), decreased appetite (42%/4%), lymphocyte count decreased (37%/23%), platelet count decreased (37%/10%), vomiting (37%/0%), dry mouth (25%/0%), fatigue (25%/0%), stomatitis (23%/2%), alopecia (21%/0%). Interstitial pneumonia occurred in 1 (2%) pt after COVID-19 infection. PK exposure was increased through dose escalation, with low systemic exposure of payload and no accumulation of YL202/BTN326 upon repeated administration. In 46 pts with at least 1 tumor assessment were evaluable for efficacy. Of the non-evaluable pts, 5 are on treatment pending first tumor assessment and 1 discontinued treatment prior to first assessment. In DL3 to DL5 dose range, ORR was 41.0% (95%CI, 25.6, 57.9), DCR was 94.9% (95%CI, 82.7, 99.4) across all tumor types; and the ORR in BC pts was 54.5% (95%CI, 23.4, 83.3), DCR was 100% (95%CI, 71.5, 100.0). Conclusions: YL202/BNT326 demonstrated encouraging efficacy in heavily pretreated locally advanced/ metastatic NSCLC and BC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05653752 . [Table: see text]

Cardiac toxicity of EGFR – 3rd generation TKI in patients with metastatic non-small cell lung cancer. Case report and literature data update

Purpose: The incidence of bronchopulmonary cancer has increased significantly in recent decades, especially in developed countries, and today it is the leading cause of death in men and the 3rd in women. The toxicities of tyrosine kinase inhibitor therapy are varied, with cardiac toxicities at the top of the pyramid. Because of the occurrence of these toxicities, depending on their intensity, the dose must be reduced or even treatment stopped. Patient and method: We present the case of a 72-year-old patient, diagnosed in 2019 with non-small bronchopulmonary neoplasm with histology of adenocarcinoma with EGFR mutation, stage IV. Results: In the oncology committee, it is decided to start targeted therapy with tyrosine kinase inhibitors of the first generation, Erlotinib, with a partial response to the treatment in the imaging evaluations, continued treatment until November 2020 when the T790M resistance mutation is detected. According to the new NCCN guidelines, therapy with the third-generation EGFR-TKI, Osimertinib, is initiated. In September 2021, the patient developed a non-ischemic acute antero-septal myocardial infarction that was complicated by LV apical aneurysm and severe LV systolic dysfunction, associated with therapy with tyrosine kinase inhibitors. Osimertinib treatment is stopped and third-line treatment with Vinorelbine is initiated. Conclusions: Investigation and permanent monitoring of patients, in treatment with 3rd generation tyrosine kinase inhibitors, who may develop cardiac toxicities, but also a good management of these toxicities, lead to both increased survival and improved status of performance.

996P Activity of OsimeRTInib in NSCLC with UNcommon EGFR Mutations: Retrospective observational multicenter study (ARTICUNO)

In 10-20% of patients (pts) with EGFR mutated NSCLC, an assorted group of uncommon mutations can be detected. These mutations confer variable sensitivity to 1st and 2nd generation TKIs, overall resulting in lower therapeutic activity. Data of Osimertinib (Osi), a 3rd generation TKI, are limited and strongly warranted.

EP08.02-169 Research of Aumolertinib Combined with Bevacizumab for Advanced NSCLC Lung Cancer with EGFR Sensitive Mutation

Aumolertinib (formerly almonertinib; HS-10296) is a novel third-generation EGFR-TKI with proved efficiency and safety for untreated NSCLC patients with EGFR sensitizing mutations in China. The efficacy of the combination of first-generation EGFR-TKI and bevacizumab was confirmed by NEJ026, JO25567 ARTEMIS studies, but the effect of 3rd generation TKI plus bevacizumab is still under debate. This study was conducted to evaluate aumolertinib plus bevacizumab for untreated NS-NSCLC patients with EGFR sensitizing mutations.

The Toxicity of Osimertinib in Cancer Therapy

Osimertinib is a novel 3rd-generation TKI which targets the EGFR in NSCLC. It inhibits the phosphorylation of EGFR, thereby inhibits proliferation of NSCLC. Thus, Osimertinib is widely used in the treatment of lung cancer, as well as other types of cancers such as glioblastoma (GBM). However, there are still some drawbacks. Osimertinib can suppress stromal cells in the bone marrow, thereby leading to the aplastic anaemia. Osimertinib can also contribute to dermatposis. Some patients are diagnosed with kidney and heart failure after the treatment, which is suspected the failures associated with the Osimertinib. Even though the drug resistance of Osimertinib is relatively low, the drug resistance cannot be completely ignored. The mechanisms of drug resistance include EGFR-dependent mechanism with the loss of T790M mutation, as well as non-EGFR-dependent mechanism due to the amplification of allele wt-EGFR and existence of allele EGFR-ex19del. In addition, the price of Osimertinib is still high in most regions. Future studies may focus on how to reduce the toxicity to organs and the drug resistance, thereby providing a direction for the fourth-generation TKI.

23P Pharmacokinetic boosting of osimertinib with cobicistat in patients with non-small cell lung cancer: The OSIBOOST trial

Exposure to osimertinib (osi), a 3rd generation TKI for treatment of non-small cell lung cancer (NSCLC) and a sensitizing epidermal growth factor receptor (EGFR) mutation is variable between patients (pts). We evaluated the boosting capacity of cobicistat (cobi), a strong Cytochrome P450 3A (CYP3A)-inhibitor, on osi exposure in pts with NSCLC and low osi plasma trough concentration.

Abstract P083: Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI

Abstract BACKGROUND Lung cancer is the most common cancer worldwide in males & a good number of patients present with metastatic disease. Though EGFR mutated patients respond to EGFR TKIs, resistance develops ultimately. Overcoming 3rd generation EGFR TKI resistance is a big challenge. METHOD 20 patients of metastatic adenocarcinoma, confirmed with core biopsy & IHC (EGFR positive) were offered Erlotinib initially. Osimertinib was offered to those who developed EGFR TKI resistance due to T790M mutation (10 cases). All 10 patients eventually developed resistance to Osimertinib. All patients were given 3 months drug free holiday & then re-challenged with Erlotinib. RESULT 4 out of 10 (40%) patients responded to the therapy. 6 patients had progression & were managed by systemic chemotherapy & radiation. CONCLUSION Literature shows up to 50% metastatic adenocarcinoma, EGFR positive patients who had developed EGFR TKI resistance to 1st & 3rd generation TKIs, responds to re-challenge with first generation TKI after a drug free holiday. In this series 40% patients responded. This approach should be tried & non-responders can be offered systemic chemotherapy & radiation. Citation Format: Suryakanta Acharya. Metastatic NSCLC -Re-challenging with first generation TKI after a drug free holiday after resistance to 3rd generation TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P083.

P48.14 Metastatic NSCLC -Re-Challenging With Fist Generation TKI After a Drug Free Holiday After Resistance to 3rd Generation TKI

Lung cancer is the most common cancer worldwide in males & a good number of patients present with metastatic disease. Though EGFR mutated patients respond to EGFR TKIs, resistance develops ultimately. Overcoming 3rd generation EGFR TKI resistance is a big challenge.

1214P High dose osimertinib in patients with advanced stage EGFR exon 20 mutation-positive NSCLC: Results from a phase II multicenter study, POSITION20

Clinical benefit to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI’s) is lacking for non-small cell lung cancer (NSCLC) patients with an EGFR exon 20 mutation (EGFRex20+), with known response rate (RR) from 0-28%, and median progression free survival (PFS) of ∼3 months to 1st and 2nd generation EGFR TKI’s (Remon, Cancer Treatment Reviews 2020). A high dose of the 3rd generation TKI osimertinib shows promising antitumor activity to EGFRex20+ in vitro. The safety and efficacy results from a multicenter single arm phase II study investigating osimertinib in EGFRex20+ NSCLC patients are reported here.

139P The impact of TP53 mutations on EGFR mt+ NSCLC IV patients treated with 3rd generation TKI on 2nd line or further line therapy: Real-world data from two certified lung cancer centers in Germany

139P The impact of TP53 mutations on EGFR mt+ NSCLC IV patients treated with 3rd generation TKI on 2nd line or further line therapy: Real-world data from two certified lung cancer centers in Germany

P76.14 Time to First Progression in Patients with NSCLC with Brain Metastases Receiving 3rd Generation TKI alone vs TKI + Brain Radiation

P76.14 Time to First Progression in Patients with NSCLC with Brain Metastases Receiving 3rd Generation TKI alone vs TKI + Brain Radiation

Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib

Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib

1344P The impact of TP53 mutations on EGFR mt+ NSCLC IV patients treated with 3rd generation TKI on second-line or further line therapy: Real world data from the German CRISP registry

1344P The impact of TP53 mutations on EGFR mt+ NSCLC IV patients treated with 3rd generation TKI on second-line or further line therapy: Real world data from the German CRISP registry

491P - Clinical outcomes of leptomeningeal metastases in EGFR-mutant lung adenocarcinoma

BackgroundLeptomeningeal metastases (LM) remain challenging for patients with non-small cell lung cancer. EGFR mutation shows a higher incidence rate of LM with poor prognosis. 3rd generation TKI has better cerebral-spinal fluid(CSF) penetration and may be a promising treatment. Here we collected LM clinical features and outcome in EGFR-mutant lung adenocarcinoma in high EGFR mutation prevalence area. MethodsThis is a retrospective observational cohort study, conducted in a tertiary medical center in Taiwan. Patients with newly diagnosed advanced lung adenocarcinoma with common EGFR mutation were enrolled. LM were diagnosed by brain imaging study or cytology study of CSF analysis. Patients without initial brain MRI imaging or patients who underwent CNS surgery initially were excluded. All the data is valid up to Dec 31, 2017. ResultsFrom 2013 to 2015, a total of 283 patients was included. All patients were treated with first-line TKIs as systemic treatment initially. Thirty-four patients had LM, accounting for 12.0% (34/283) of this cohort. Only four patients in the LM group (11.7%) received CSF study, and three of them showed malignant cells in their CSF. Patients with LM had median overall survival(OS) 26.2 months, whereas patients with brain tumor progression had median OS 42.3 months. (p = 0.002) For patients with LM, the median OS after LM is 5.1 months. Patients with younger age(HR0.63[0.45-0.90], p = 0.01) and initial M1b(HR 2.86[1.81-4.53], p < 0.001) were associated with higher risk or intracranial progression. Among 34 patients, 6 patients received 3rd generation TKI and revealed significant better OS than those without 3rd TKI. (OS 15.3 months vs 3.7 months, p = 0.03). ConclusionsLM show poor prognosis for patients with EGFR-mutant lung adenocarcinoma, compared with other types of brain metastases. Younger age and initial M1b associated with higher risk. Patients with 3rd generation TKI may bring benefit to these patients. Legal entity responsible for the studyThe authors. FundingTaipei Veterans General Hospital. DisclosureC-H. Chiu: Honoraria (self): AstraZeneca; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Roche. All other authors have declared no conflicts of interest.

Investigation of the mechanisms of resistance to osimertinib in patients with T790M-associated NSCLC

Abstract Background Osimertinib (Osi) is a 3rd generation TKI that crosses the blood-brain barrier (BBB), which has been shown to be effective in both the second and first line of treatment in patients with NSCLC with an EGFR mutation. In use of Osi in patients with T790M associated progression during therapy with earlier TKIs, the median PFS was 10.1 months. The duration of treatment may vary significantly for each patient. The study of the mechanisms of resistance to 3rd generation TKIs is the subject of clinical studies, among the most common variants of resistance - the appearance of the gate-keeper mutation C797S - in 7% of cases. Methods It is prospective, single-center study we examined the appearance of resistance in patients receiving Osi treatment.The search for the C797S mutation was carried out using an original diagnostic platform based on real-time PCR, using the BioRad Real-Time CFX96 amplifier. Primers and fluorescent probes were synthesized by Applied Biosystems compony. The study included patients with progression during therapy with Osi. Before treatment, and then every 2 months until progression of the disease appease, blood sampling was performed to conduct a qualitative assessment of ctDNA (ex19del, L858R, T790M, C797S). Results From August 2016 to August 2019, in 12/22 patients, progression of the disease during the Osi. Emong them, 66.7% (7/12) are women, 33.3% (4/12) are men. The average age is 64.6 years (55-80). 1/12 smoked for over 30 years. The molecular genetic profile in 58.3% (7/12) of the patients is ex19del, 33.3% (4/12) of L858R, 8.4% (1/12) is a combination of rare mutations G719S + S768I. The median PFS during the Osi treatment was 9.6 months. (0.7 - 18.4).The analysis of ctDNA was performed in 11/12 patients: an activated mutation was detected in all cases, 1/12 recorded the mutation C796S (NGS), T790M and C797S (cis/ trans) were not detected.Histological material was taken from 4/12 patients, 2 of which showed the transformation of the tumor into small cell lung cancer. Conclusions The investigation of appearence the resistance mechanisms in the treatment with osimertinib did not reveal the EGFR C797S mutation, which may be associated with a small number of patients included in the study.Grant supported RUSSCO / RakFond 2018-01-YS-ECI. Legal entity responsible for the study St. Petersburg Clinical Research Center of Specialized Types of Care (Oncology). Funding RakFond (Russia). Disclosure All authors have declared no conflicts of interest.

P2.14-30 Predictive Value of ctDNA in Patients with EGFR Positive NSCLC Receiving 3rd Generation TKI

The third generation TKI (osimertinib) according to AURA III trial results achieved longer PFS compared to standard platinum based chemotherapy in patient’s resistant to 1-2 generation TKIs due to T790M mutation (8.5 vs 4.2 months). The evolution of resistance profile during thins therapy can be analyzed based on ctDNA. In this study patients with metastatic EGFR mutated NSCLC, with a confirmed disease progression during treatment with 1/2 generation TKIs, T790M positive which included patients received osimertinib 80 mg daily. Before the treatment and then every 2 months, whole blood was taken, for qualitative assessment of ctDNA dynamics by RT-PCR. The aim of the study was to assess the relationship between the disappearance of T790M + ctDNA and the time to progression on osimertinib. From August 2016 to December 2018 22 patients with T790M positive progression were identified. 18/22 (81.9%) were women, 4/22 (18.1%) - men. The mean age was 61.2 years (50-75). Only 1/22 had a smoking history >30 pack/years. Primary activating mutations in EGFR gene were ex19del, L858R and G719S + S768I in 16, 5 and 1 patients respectively. Median PFS on the first line TKI was 21.7 months (CI 95%, 10.8 – 53.3). In 59.1% (13/22) progressive disease was characterized by the appearance of new metastases and in 40.9% (9/22) by the growth of previously identified metastases. 22 patients were evaluable for response. PR and SD were achieved in 11/20 (50%) and 10/20 (45/5%) respectively. Median PFS was in a whole group 16.7 months (CI 95%, 11.4 - 22.0). T790M in ctDNA was negative after 2 months of osimertinib treatment in 12/22 patients. Median PFS was 18.9 months (CI 95%, 14.8–19.7) in patients with undetectable T790M in ctDNA after 2 month of therapy compared to 8.0 months (CI 95%, 4.2 – 11.8) in patients remaining ctDNA T790M positive. No clinical factors were associated with the disappearance of ctDNA by statistical analysis. The disappearance of T790M + ctDNA after 2 months osimertinib therapy is predictive of greater PFS in patients with EGFR mutation positive NSCLC, receving of 2nd line.

Results of the phase 1b study of ABBV-399 (telisotuzumab vedotin; teliso-v) in combination with erlotinib in patients with c-Met+ non-small cell lung cancer by EGFR mutation status.

3011 Background: Telisotuzumab vedotin (ABBV-399; teliso-v [T]) is a c-Met–targeted antibody and MMAE drug conjugate. Activity of T was shown in late-line c-Met+ non-small cell lung cancer (NSCLC) irrespective of EGFR mutation (M+) status. We present mature data from the T+ erlotinib (E) cohort of a phase 1b study (NCT02099058) by EGFR M+ status. Methods: T was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg IV Q3W, and E at 150 mg PO QD/prior tolerated dose in adult patients (pts) with advanced NSCLC. Efficacy-evaluable pts were c-Met+ (central lab IHC H-score ≥150 or local lab MET amplification/Ex 14 skipping) and had ≥1 postbaseline scan or discontinued study. EGFR M+ was defined as del19 or L858R by local lab. PK was assessed. Results: As of Dec 2018, 42 NSCLC pts received T+E; 37 were c-MET+ (36 evaluable; 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 pts (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (Gr; ≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Gr 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Gr ≥3 (≥10%) AE: pulmonary embolism (14%). PK of T+E was similar to single-agent T. The table presents efficacy data. Conclusions: These data suggest acceptable safety and promising activity of T+E and support further study in EGFR M+ c-Met+ NSCLC pts for whom frontline EGFR TKI failed. Clinical trial information: NCT02099058. [Table: see text]

A phase I/II study of blinatumomab in combination with pembrolizumab for adults with relapsed refractory B-lineage acute lymphoblastic leukemia: University of California Hematologic Malignancies Consortium Study 1504.

TPS7064 Background: Outcomes for adults with relapsed/refractory B-cell ALL (R/R B-ALL) remain poor despite new targeted therapies. Blinatumomab is an anti-CD19/CD3 bifunctional T-cell engaging antibody that was superior to conventional salvage therapy for remission and overall survival in a Phase III study of patients with R/R B-ALL. The CR/CRh rate for blinatumomab was 65.5% with &lt; 50% marrow lymphoblasts but dropped to 34.4% with ≥ 50% marrow lymphoblasts. Clinical and pre-clinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow may mediate resistance to blinatumomab by inhibiting T-cell activation. We hypothesize that addition of pembrolizumab will improve CR/CRh rates to blinatumomab in R/R B-cell ALL. Methods: We are conducting a phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with R/R B-ALL and a high bone marrow lymphoblast percentage (NCT 03160079). The primary endpoint is ORR (CR+CRh) after 1-2 cycles with secondary endpoints of AEs, MRD-negative CR/CRh rate, 2-year DFS, 2-year OS, and allogeneic HCT rate. Exploratory studies are evaluating cytokine expression, PD-1 expression on T-cells, PD-L1 and PD-L2 protein expression on lymphoblasts, and T-cell populations at diagnosis and in response to therapy. Eligibility includes: adults with R/R CD19+ B-ALL after ≥ 1 prior line of therapy, R/R Ph+ B-ALL must fail a 2nd- or 3rd-generation TKI or be TKI intolerant, &gt; 50% lymphoblasts on screening bone marrow sample. Blinatumomab is given by continuous IV at 9 mcg/day days 1-7 of cycle 1, 28 mcg/day days 8-28 of cycle 1, then at 28 mcg/day days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles will complete 5 cycles. Patients not in CR/CRh after 2 cycles of therapy or progressing after Day 15 of cycle 1 go off study. CNS prophylaxis with IT methotrexate is given at screening and once per cycle. A phase I run-in of 3-6 patients precedes accrual of 18-21 patients for a target of 24. The study opened in July 2017 and 4 patients have been treated. No DLTs have occurred to date. Clinical trial information: NCT03160079.

Standard dose osimertinib for erlotinib refractory T790M-negative EGFR-mutant non-small cell lung cancer with leptomeningeal disease.

Leptomeningeal spread in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations who experience disease progression on TKIs portends a poor prognosis. Mutation profiling of tumour DNA in cerebrospinal fluid (CSF) samples can be used to determine the presence of the EGFR T790M resistance mutation, indicating that osimertinib, a CNS-penetrating 3rd generation TKI may be efficacious. Eight patients on EGFR TKIs who progressed with cytology-proven leptomeningeal disease at our institution were studied. EGFR mutations were profiled in CSF using droplet digital PCR (ddPCR) and compared to matched plasma samples. Clinical characteristics and survival outcomes on subsequent therapies tailored to ddPCR analysis were reported. None of the four patients who developed leptomeningeal disease while receiving 1st generation EGFR TKIs developed the EGFR T790M mutation in CSF. One patient who did not have extra-cranial disease and was EGFR T790M-negative in both plasma and CSF was nevertheless treated with standard-dose osimertinib, and achieved a rapid and durable response lasting 9 months to date. Three patients developed leptomeningeal disease on osimertinib, with one patient developing the EGFR C797S mutation in a cis-allelic conformation with the EGFR T790M mutation in plasma. Standard-dose osimertinib resulted in a clinically meaningful response in a patient with EGFR T790M-negative 1st generation EGFR TKI refractory leptomeningeal disease. Next generation sequencing and ddPCR has a role at identifying the C797S mutation and its allelic conformation with the T790M mutation with clinical implications.