Mobocertinib is a potent first-in-class tyrosine kinase inhibitor (TKI) designed to target EGFR exon 20 insertion (EGFRex20ins) mutations. We report first results from the EXCLAIM extension cohort of a phase 1/2 study (NCT02716116) and results in patients with EGFRex20ins-mutant NSCLC who received prior platinum-based therapy from the dose-escalation/expansion parts of the study and the EXCLAIM extension cohort.

The population of EGFR exon 20 insertion (ex20ins) mutations includes a diverse array of insertion variants and represents 5%-10% of EGFR mutations in non–small cell lung cancer (NSCLC). Specific targeted therapies are not available for patients with EGFR ex20ins+ NSCLC, regardless of insertion variant status; however, mobocertinib and amivantamab are currently in development. Identifying patients with EGFR ex20ins is challenging due to the limited coverage of polymerase chain reaction (PCR) assays and relatively recent use of next-generation sequencing (NGS).

Standard dosing of brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor for treating ALK+ non-small cell lung cancer is 90 mg once daily for 7 days then escalated to 180 mg on Day 8 as tolerated. Among patients receiving this standard dose, 29% in the post-crizotinib ALTA trial and 38% in the tyrosine kinase inhibitor (TKI)-naïve ALTA-1L trial required a dose reduction. Asymptomatic laboratory abnormalities including creatine phosphokinase, amylase or lipase elevations were common causes of dose reductions in these studies.

Anaplastic Lymphoma Kinase (ALK)-targeted tyrosine kinase inhibitors have shown to be effective as first-line (1L) treatment of ALK-positive non-small cell lung cancer (NCSLC). However, head-to-head comparisons between most available ALK inhibitors are lacking. The objective of this study was to conduct a systematic literature review (SLR) and meta-analyses to estimate the relative efficacy of brigatinib compared to other approved ALK inhibitors or chemotherapy in patients with locally advanced or metastatic ALK inhibitor-naïve ALK-positive NSCLC (≤1 prior chemotherapy regimen was allowed).

Abstract Introduction/Objective Epidermal growth factor receptor (EGFR) mutations are common in non-small cell lung cancer (NSCLC). EGFR exon 20 insertions (EGFRex20ins), a rare subset of EGFR mutations, are refractory to tyrosine kinase inhibitors. With the development of targeted therapies for EGFRex20ins, such as mobocertinib, molecular testing is required to optimize treatment. A better understanding of real-world EGFR detection patterns is needed to maximize patient outcomes. Methods/Case Report This retrospective study describes EGFR testing and EGFRex20ins detection patterns in patients with NSCLC in the United States. The Flatiron Health electronic health record database was used to identify patients ≥18 years, with advanced NSCLC, and with ≥2 clinic visits between 01/01/2011 and 12/31/2020. Baseline demographics, clinical characteristics, EGFR testing, and EGFRex20ins detection rates by sex, race, and smoking history were summarized. Results (if a Case Study enter NA) A total of 67,281 patients with NSCLC were identified. EGFR testing increased from 44% in 2011 to 77% in 2020. Of all patients, 44,926 (66.8%) were tested: 50.8% female; 3.3% Asian; 16.0% never-smokers. Of all patients, 22,355 (33.2%) were not tested: 41.4% female; 1.2% Asian; 7.5% never-smokers. Of those tested, 6,245 (13.9%) patients had EGFR mutations: 65.9% female; 11.8% Asian; 48.4% never-smokers. EGFRex20ins detection rates changed from 0.6% in 2011 to 1.0% in 2019 and 0.7% in 2020. Of those tested, 304 patients had EGFRex20ins: 58.2% female; 8.2% Asian; 50.3% never-smokers. EGFR testing was higher in females (71.2%) than males (62.8%), never-smokers (84.5%) than those with a smoking history (64.6%), and Asian patients (84.2%) than White (66.6%), Black (65.4%), or other patients (69.5%). Of those tested, EGFRex20ins mutations were detected in 0.8% of females (males: 0.6%), 2.2% of never-smokers (with smoking history: 0.4%), and 1.7% of Asians (White: 0.6%, Black: 0.6%, other patients: 0.7%) had EGFRex20ins. A similar trend was observed for EGFR mutations with higher proportions of females, never-smokers, and Asian patients affected. Conclusion EGFR testing and EGFRex20ins detection rates have increased. However, not all patient subgroups were tested at the same rate and undertesting occurred in all subgroups. Further education of specialists diagnosing NSCLC is warranted to ensure all patients receive biomarker testing and benefit from emerging EGFRex20ins- targeted therapies.

Epidermal growth factor receptor exon 20 insertions (EGFRex20ins) are an uncommon subset of EGFR-activating mutations that are associated with a lack of responsiveness to tyrosine kinase inhibitor (TKI) therapy. With the clinical development of TKIs and monoclonal antibodies targeting EGFRex20ins, broad molecular profiling is needed to direct patients to these therapies. We describe real-world EGFRex20ins detection patterns in patients with advanced non-small cell lung cancer (NSCLC) in the United States.

Non–small cell lung cancer (NSCLC) with the anaplastic lymphoma kinase-positive (ALK+) mutation is a rare subtype of NSCLC. Available treatments include several ALK inhibitor therapies (eg, crizotinib, alectinib, ceritinib, and brigatinib) with some showing health-related quality of life (HRQoL) benefits. HRQoL, including disease- and treatment-related symptoms and impacts, is a significant factor when making treatment decisions. However, qualitative research on HRQoL among ALK+ patients is limited.

Patients whose lung cancers harbor anaplastic lymphoma kinase (ALK) rearrangements are sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Several treatment guidelines recommend molecular testing to identify ALK-positive patients who are eligible for ALK TKI therapy. This study assessed real-world ALK testing patterns among community practices in the United States in patients with advanced non-small cell lung cancer (NSCLC) and explored treatments received prior to receiving test results in patients with ALK-positive NSCLC.

At ALTA-1L (NCT02737501) first interim analysis (IA1), brigatinib demonstrated superior BIRC-assessed PFS and iPFS vs crizotinib. We report IA2 results, planned at ∼75% of 198 expected PFS events. Patients with TKI-naive advanced ALK+ NSCLC were randomized 1:1 to brigatinib 180 mg qd (7-day lead-in at 90 mg) or crizotinib 250 mg bid. Endpoints: Primary, BIRC-assessed PFS (RECIST v1.1); secondary included confirmed ORR and iORR, and iPFS (BIRC). 275 patients were randomized (brigatinib/crizotinib, n=137/138); median age, 58/60 years; prior chemotherapy, 26%/27%; baseline brain metastases (BIRC), 34%/36%; brain radiotherapy, 13%/14% (WBRT/SRS balanced across arms). At data cutoff (28 June 2019, median follow-up [brigatinib/crizotinib], 24.9/15.2 months, 150 PFS events): BIRC-assessed PFS HR, 0.49 (95% CI, 0.35–0.68, log-rank P<0.0001); brigatinib mPFS, 24.0 months (95% CI, 18.5–NE) vs crizotinib 11.0 months (9.2–12.9). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31–0.61, median 29.4 vs 9.2 months). OS was immature (total events: 33/37, brigatinib/crizotinib). In patients with baseline brain metastases, PFS HR was 0.25; data were less mature in brigatinib patients without brain metastases. Additional results in Table. Radiological overall disease progression occurred in (brigatinib vs crizotinib) 54 (39%) vs 74 (54%) patients (BIRC) and 50 (36%) vs 84 (61%) (investigator); of these, brain was first site of progression more frequently with crizotinib vs brigatinib: 31 (42%) vs 17 (31%) patients (BIRC); 22 (26%) vs 7 (14%) (investigator). Most common TEAEs grade ≥3: brigatinib: increased CPK (24.3%) and lipase (14.0%), hypertension (11.8%); crizotinib: increased ALT (10.2%), AST (6.6%), lipase (6.6%). Brigatinib significantly delayed median time to deterioration vs crizotinib for global health score/QoL (log-rank P=0.0485), emotional and social functioning, fatigue, nausea and vomiting, appetite loss, constipation. Brigatinib demonstrated superior systemic and intracranial efficacy vs crizotinib in all patients with TKI-naive ALK+ NSCLC and in patients with baseline brain metastases.

Cancer immunotherapies are new treatment options in advanced non-small cell lung cancer (NSCLC). Evidence of immuno-oncology (IO) therapy efficacy in tumors with activating mutations, such as anaplastic lymphoma kinase (ALK) rearrangements, is lacking. This retrospective study describes the characteristics of ALK+ NSCLC patients treated with IO therapy and assesses treatment outcomes in these patients (time to treatment discontinuation, real-world progression-free survival [rwPFS]). The Flatiron Health Electronic Health Record (EHR)−derived database (Jan 2011−Jun 2018) was used to identify patients with advanced ALK+ NSCLC who had received IO therapies (nivolumab, pembrolizumab, atezolizumab, durvalumab). Discontinuation of IO therapy was defined as switch to an ALK TKI or chemotherapy or addition of chemotherapy (for IO monotherapy), death, gap between IO administrations >120 days, or gap between last IO therapy administration and last follow-up date of >120 days. rwPFS was estimated as the time from treatment initiation to progression (abstracted from clinician notes and radiology reports) or death. Time to discontinuation and rwPFS were analyzed using Kaplan-Meier methods. Of 593 ALK+ NSCLC patients with follow-up between 2015−2018, 83 (14%) patients were treated with IO therapy. Mean age was 60.3 years, with 65.1% of patients diagnosed at stage IV, and 61.4% patients receiving nivolumab. Of the 83 IO-treated patients, 50.6% received IO therapy before first ALK TKI, and 38.6% were treated with IO therapy after ≥2 ALK TKIs. Median (95% CI) time to discontinuation of IO therapy was 2.17 mo (1.41−3.32) and rwPFS was 2.34 mo (1.55−3.09). We identified ALK+ NSCLC patients who received IO therapy, half of whom were treated post-ALK TKI. Time to discontinuation of IO therapy was short, and real-world effectiveness (rwPFS) was limited. These results point to IO therapy's relative futility in ALK+ NSCLC patients. Compared to IO therapy, several approved ALK inhibitors have shown better effectiveness in both first and later lines of therapy. However, the optimal sequencing of ALK inhibitors with other therapies, including chemotherapy and IO therapy, remains unclear.

The ALKConnect Patient Insight Network (www.alkconnect.com) is a patient-centered online registry that provides support to and collects information from patients living with Anaplastic Lymphoma Kinase-Positive (ALK+) Non-Small Cell Lung Cancer (NSCLC). The objectives of this study were to: (1) describe the characteristics of patients in ALKConnect; (2) quantify patients' preferences, ALK+ NSCLC symptom burden, and health-related quality of life (HRQoL); and (3) determine whether disease treatment and employment status were associated with HRQoL. Study inclusion criteria were US adults (18 years or older) living with ALK+ NSCLC who have internet access, and willingness to answer e-surveys. Cross-sectional 'real-world' data that were collected included demographics, disease history and status, comorbidities, treatments, patient preferences, and HRQoL (MD Anderson Symptom Inventory lung cancer module [MDASI-LC]), reported as symptom severity and interference in activities of daily living (walking, activity, work, relations with others, enjoyment, and mood) caused by symptoms. Data were reported descriptively overall and by subgroups of interest (e.g., treatments, employment status) where sample sizes permitted. Associations between patient treatment history and employment status and HRQoL were analyzed. Data for 104 patients were available. Median age was 53.0 years (range 22-90), 67.3% were female, 84.0% were White (n=84), 12.0% were Asian (n=12), and 40.0% (n=40) were employed. Most patients were treated with ALK tyrosine kinase inhibitors (TKIs) (83.7% [n=87] ALK TKI only). Among treatment-associated preferences, preventing disease progression, shrinking tumor size, and maintaining HRQoL were perceived to be the most important treatment attributes. An additional 3-month delay in disease progression was perceived to be meaningful by 57.7% (n=60) of patients. MDASI-LC inventory data (from n=75 patients) showed that the most bothersome patient-reported symptoms were fatigue, sleep disturbance, drowsiness, difficulty remembering, and constipation. Interference on patient HRQoL was greatest for work and activity. Statistically-significant associations were observed between HRQoL and treatment with ALK TKIs (Symptom Severity p=0.0062, Interference p=0.0016), number of prior ALK TKIs (Symptom Severity p=0.1487, Interference p=0.0137), and employment status (Symptom Severity p=0.0201, Interference p=0.0210). ALKConnect gathered humanistic burden data directly from patients with ALK+ NSCLC. Participants reported that the most burdensome symptoms were fatigue, sleep disturbance, and drowsiness, and that symptoms interfered most with work and general activity. A 3-month delay in cancer progression and HRQoL were important treatment attributes. Patients' HRQoL was positively associated with ALK TKI treatment and the ability to maintain employment status, suggesting that these aspects may be important for ALK+ NSCLC patients' well-being.

Results from ALTA-1L (NCT02737501) showed that brigatinib vs crizotinib as first-line ALK therapy significantly improves progression-free survival (PFS; HR: 0.49, 95% CI, 0.33, 0.74) in advanced ALK+ NSCLC. HRQoL was evaluated as a secondary objective. ALK+ NSCLC patients were randomized 1:1 to brigatinib or crizotinib as first-line ALK therapy. HRQoL was assessed with the EORTC QLQ-C30 and LC13. Change from baseline, duration of improvement, and time to worsening were analyzed in the ITT-PRO population (n=131 for both groups). HRQoL compliance was >90% for both groups. Brigatinib substantially improved overall HRQoL vs crizotinib, as demonstrated by the estimated mean difference on change from baseline (4.1, P<0.05; Figure 1) and duration of improvement for GHS/QoL (HR=0.16, P<0.001; Figure 2), which was also supported by improvement in several functional domains and symptoms (Figure 1). No domains significantly favored crizotinib. Similar results were also observed in patients with baseline CNS metastases.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Consistent with the prolongation of PFS seen in first-line treatment of advanced ALK+ NSCLC, brigatinib improved HRQoL and prolonged the duration of improvement in GHS/QoL, and the majority of functional and symptom domains vs crizotinib.

Mutations in the epidermal growth factor receptor (EGFR) gene have been identified in 10-50% of patients with non-small cell lung cancer (NSCLC), and 2-10% are exon 20 insertion mutations. This study describes real-world characteristics, treatment patterns, and overall survival (OS) of NSCLC patients with EGFR exon 20 insertions. Flatiron Health electronic health record data from 1/2011-4/2018 were used for this retrospective study. Treatment-naïve (TN) and relapsed/refractory (RR) patients with advanced/metastatic NSCLC with EGFR exon 20 insertion mutation aged ≥18 years at treatment initiation were included. Patient characteristics were described, and Kaplan-Meier analyses were used to assess OS for TN and RR patients. There were 128 TN and 71 RR patients identified. Median age was 66.5 and 65.0 years for TN and RR patients, respectively, and over half were female (TN: 59.4%, RR: 53.5%). Among 83 TN and 47 RR patients with known ECOG score at advanced diagnosis, most had score 0-1 (TN: 56.3%, RR: 62.0%). Central nervous system metastases were observed in 35.2% of TN and 33.8% of RR patients. 45.3% of TN patients and 23.9% of RR patients received chemotherapy only. Approximately 20% of TN and RR patient were treated with EGFR TKI only. Only 6.3% of TN patients received any immuno-oncologic therapy (IO) or combination, while this was higher in RR patients (29.6%). Overall, median OS was low at 16.2 months for TN patients, and 12.5 months for RR patients. Treatment with any IO was associated with poor survival in TN (6.1 months) and RR (8.0 months) patients. OS of patients with EGFR exon 20 NSCLC remains poor. In TN patients, chemotherapy was the most common treatment, followed by EGFR TKIs. Treatment patterns were more diverse in RR patients. This study demonstrated unmet medical need for patients with NSCLC with EGFR exon 20 insertion mutation.

Anaplastic lymphoma kinase (ALK) gene rearrangements occur in 3 to 8% of non-small cell lung cancer (NSCLC) cases. Targeted therapy options for ALK+ NSCLC patients have increased recently and are associated with improved survival. This study aimed to describe the real-world use of brigatinib, particularly after crizotinib and other ALK-tyrosine kinase inhibitors (TKI), where most brigatinib patients were found in this study. Adult (≥18 years) patients with ≥1 claim for brigatinib (index claim) after crizotinib were identified between 01-Jan-2011 and 30-Jun-2018 from IQVIA's US-based Longitudinal Patient-Centric Pharmacy Claims Database. Patients had ≥6 months of observation before crizotinib and were continuously followed post-index for use of brigatinib and until discontinuation (≥90-day gap in brigatinib therapy, switch to another ALK-TKI therapy, or the end of follow-up of brigatinib). Brigatinib on-treatment rates at 6- and 12-months post-index were estimated using Kaplan-Meier analysis in subgroups with > 50 patients. The final sample consisted of 92 post-crizotinib brigatinib patients, most of whom were treated with crizotinib and ≥ 1 second generation (2G) ALK-TKI inhibitor (n=72); twenty patients received crizotinib only prior to brigatinib. Among the 72 patients treated with crizotinib and ≥1 2G ALK-TKI median (range) age at brigatinib initiation was 58.1 (30-85) years; 68.1% of the sample was female and most had third party insurance (51.4%). Mean (SD) post-index follow-up time was 6.7 (4.2) months. Sixty patients (56.9%) received crizotinib and alectinib (± ceritinib), while twelve (16.7%) received only crizotinib and ceritinib prior to brigatinib. Median brigatinib treatment duration was 8.3 months in patients with prior crizotinib and ≥1 2G ALK-TKI (n=72); 64.8% and 49.3% of these patients were still on brigatinib 6- and 12- months after initiation. In the subgroup of patients with crizotinib and alectinib ± (ceritinib) prior to brigatinib (n=60), median duration of brigatinib treatment was also 8.3 months; 66.6% and 48.1% were still on brigatinib 6- and 12-months after initiation. This US-based real-world study provides early insight into the use of recently approved brigatinib in NCSLC in the post crizotinib setting. These results indicate that use of brigatinib may be associated with potential clinical benefit with patients staying on therapy for a significant duration of time post a 2G ALK-TKI inhibitor. The duration of brigatinib in earlier lines remains to be investigated in future studies when larger sample sizes are available.

ALK+ NSCLC is a subset of NSCLC present in ∼3-5% of NSCLC patients. Little is known about ALK+ NSCLC patients’ unique journeys, their perspectives on the burden of disease, and their ‘real-world’ treatment experiences. Online patient networks provide opportunities to gain valuable insights into outcomes meaningful to patients, directly from patients. The objective of this study is to develop an ALK+ NSCLC patient network to facilitate patient interaction and to conduct patient-centered research including understanding unmet needs, patient preferences, health-related quality of life (HRQoL), and product differentiation. The ALKConnect Patient Insights Network (www.alkconnect.com) will be a patient-focused registry that directly collects information from patients living with ALK+ NSCLC. Patients meeting study criteria will be enrolled in the online survey over a 2-year period. Inclusion criteria are US, adult, English-speaking patients with ALK+ NSCLC providing written, informed consent, internet access, and willing to answer regular e-surveys. Retrospective and cross-sectional ‘real-world’ data that will be collected include demographics, clinical characteristics including ALK+ NSCLC disease history and status, comorbidities, past and present treatment experiences and outcomes, quality of life, patient preferences, healthcare resource use, and work productivity. Supplementary data may be collected through uploading of electronic medical records. The ALKConnect Patient Insights Network will systematically characterize the natural history of ALK+ NSCLC and its treatment and the overall impact on patients. The data collected will be reported descriptively for the population overall and by subgroups of interest (e.g., age, sex) where sample sizes permit. The associations between treatment history/disease status and patient-reported outcomes including symptom severity, HRQoL (e.g., responses to the MD Anderson Symptom Inventory lung cancer module [MDASI-LC]), healthcare resource use, and work productivity will be analyzed. Longitudinal trends will be evaluated to enable a better understanding of the impact of ALK+ NSCLC over time. All de-identified information gathered from ALKConnect will be shared with the ALK+ NSCLC community, including patients, caregivers, healthcare professionals, advocacy organizations, and fellow researchers. We present ALKConnect, an online ALK+ NSCLC patient insights network directly from patients. ALKConnect will provide patients with ALK+ NSCLC opportunities to share their treatment experiences, disease burden, HRQoL, and preferences. Through dissemination to scientific and medical communities, researchers will gain first-hand insights into ALK+ NSCLC patients’ experiences of care, and into opportunities for addressing patients’ unmet needs.