Mobocertinib in patients with EGFR exon 20 insertion-positive non-small cell lung cancer (MOON)

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24–45). The response rate in treatment-naïve patients was 27% (95% CI, 8–58). The median progression-free and overall survival was 5 months (95% CI, 3.5–6.5) and 12 months (95% CI, 6.8–17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP) : a retrospective analysis from an early access program

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal–epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77years (range, 48–91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47–69), whereas it was 68% (95% CI, 50–82) in treatment-naïve and 50% (95% CI, 35–65) in pretreated patients. The median progression-free survival was 9.5months (95% CI, 4.7–14.3), whereas it was 10.6months (95% CI, 5.5–15.7) in first-line and 9.1months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0months, the median overall survival was 18.2 months (95% CI, 13.2–23.1). In patients with measurable brain metastases (n=11), the intracranial ORR was 46% (95% CI, 17–77). Capmatinib showed a manageable safety profile. Grade⩾3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting

Real-world survival outcomes with immune checkpoint inhibitors in large-cell neuroendocrine tumors of lung

Background Little is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC).Methods 125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured.Results With a median follow-up of 11.8 months (mo) (IQR 7.5–17.9) and 6.0mo (IQR 3.1–10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02—unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04—adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4).Conclusions With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC

Stereotactic body radiation therapy (SBRT) for the treatment of primary lung cancer in recipients of lung transplant

Lung transplantation is a life-saving treatment for patients with end stage lung disease. There may be a higher incidence of lung cancer in lung transplant recipients, and these cancers tend to be diagnosed at a more advanced stage. There is very little data on the safety and efficacy of stereotactic body radiation therapy (SBRT) for lesions in the native lung in lung-transplant recipients

Tyrosine Kinase Inhibitors as a Treatment of Symptomatic CNS Metastases in Oncogene-Driven NSCLC

Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment approaches can potentially delay systemic treatment (surgical intervention) or result in neurocognitive impairment (radiotherapy). Recently, next-generation tyrosine kinase inhibitors (TKIs) have demonstrated remarkable intracranial activity. However, most clinical trials did not enroll patients suffering neurological symptoms. Our study aimed to assess the CNS activity of targeted therapies in this patient population. We present a case series of nine NSCLC patients with either EGFR mutation or ALK rearrangement and symptomatic CNS metastases that were treated with TKIs. Clinicopathological characteristics, treatment, and outcomes were analyzed. Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9). Additionally, the majority of patients had leptomeningeal disease (6/9) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache, and confusion. Most patients (6/9) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. In conclusion, upfront use of next-generation TKIs in patients with oncogene-driven NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option

Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC : a retrospective chart review (REFLECT)

Background. Immunotherapy with immune checkpoint inhibitors (ICIs) recently became the standard treatment for patients with advanced non-small cell lung cancer (NSCLC). Here, we present the first results of a real-world observational study on the effectiveness of ICI monotherapy in patients with advanced NSCLC treated at a single academic center in a Central and Eastern European (CEE) country. Materials and methods. Overall, 66 consecutive patients with advanced NSCLC treated with ICIs in everyday clinical practice, either with first-line pembrolizumab (26 patients) or second-line atezolizumab, nivolumab, or pembrolizumab (40 patients), from August 2015 to November 2018, were included. All data were retrieved from a hospital lung cancer registry, in which the data is collected prospectively. Results. Included patients had a median age of 64 years, most were male (55%), 6% were in performance status >/=2, and 18% had controlled central nervous system metastases at baseline. In first-line, the median progression-free survival (mPFS) was 9.3 months, while the median overall survival (mOS) was not reached. The 1-year overall survival (OS) was 62%. In second-line, the mPFS and mOS were 3.5 months and 9.9 months, respectively, with a 1-year OS of 35%. In the overall population, adverse events of any grade were recorded in 79% of patients and of severe grade (3-4) in 12% of patients. Conclusion. The first real-world outcomes of NSCLC immunotherapy from a CEE country suggest comparable effectiveness to those observed in clinical trials and other real-world series, mainly coming from North America and Western European countries. Further data to inform on the real-world effectiveness of immunotherapy worldwide are needed

Treatment patterns, testing practices, and outcomes in the pre-FLAURA era for patients with EGFR mutation-positive advanced NSCLC: a retrospective chart review (REFLECT)

Introduction: For epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC), EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred first-line (1 L) treatment in the advanced setting. Osimertinib, a third-generation EGFR-TKI, received full approval in 2017 for second-line (2 L) treatment of EGFR T790M-positive NSCLC. The REFLECT study characterizes real-world treatment/testing patterns, attrition rates, and outcomes in patients with EGFRm advanced NSCLC treated with 1 L first-/second-generation (1G/2G) EGFR-TKIs before 1 L osimertinib approval. Methods: Retrospective chart review (NCT04031898) of European/Israeli adults with EGFRm unresectable locally advanced/metastatic NSCLC, initiating 1 L 1G/2G EGFR-TKIs 01/01/15-30/06/18 (index date). Results: In 896 patients (median follow-up of 21.5 months), the most frequently initiated 1 L EGFR-TKI was afatinib (45%). Disease progression was reported in 81%, including 10% (86/896) who died at 1 L. By the end of study, most patients discontinued 1 L (85%), of whom 33% did not receive 2 L therapy. From index, median 1 L real-world progression-free survival was 13.0 (95% confidence interval (CI): 12.3-14.1) months; median overall survival (OS) was 26.2 (95% CI: 23.6-28.4) months. 71% of patients with 1 L progression were tested for T790M; 58% were positive. Of those with T790M, 95% received osimertinib in 2 L or later. Central nervous system (CNS) metastases were recorded in 22% at index, and 15% developed CNS metastases during treatment (median time from index 13.5 months). Median OS was 19.4 months (95% CI: 17.1-22.1) in patients with CNS metastases at index, 24.8 months (95% CIs not available) with CNS metastases diagnosed during treatment, and 30.3 months (95% CI: 27.1, 33.8) with no CNS metastases recorded. Conclusion: REFLECT is a large real-world study describing treatment patterns prior to 1 L osimertinib availability for EGFRm advanced NSCLC. Given the attrition rates highlighted in the study and the impact of CNS progression on outcomes, offering a 1 L EGFR-TKI with CNS penetration may improve patient outcomes in this treatment setting

Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature

Abstract Background Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non‐small cell lung cancer (NSCLC). Methods A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next‐generation sequencing in 01/2015‐8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression‐free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log‐rank and Cox regression analyses. Results Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum‐based chemotherapy. Conclusion Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively

Thrombosis, anticoagulation and outcomes in malignant superior vena cava syndrome

Anticoagulation is often used in superior vena cava syndrome (SVCS) associated with cancer (i.e malignant SVCS), even without thrombosis, but its effect on outcomes has not been reported. We aimed to determine factors and outcomes associated with thrombosis and anticoagulation in malignant SVCS. Patients with malignant SVCS diagnosed on computerized tomography (CT) were retrospectively included, indexed at diagnosis and followed for 6 months using medical records. The cohort included 183 patients with malignant SVCS of which 153 (84%) were symptomatic. Thirty of the 127 patients (24%) with a reviewable baseline CT had thrombosis of the SVC or tributaries at diagnosis. Patients with baseline thrombosis more often had symptomatic SVCS (