No abstract

Background Osimertinib is a selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) with increased penetration across the blood brain barrier compared to previous EGFR TKIs and thus a 52% reduction in the risk of intracranial disease progression is seen when it is used as 1st line of therapy compared to gefitinib and erlotinib. It is also efficient as 2 nd line therapy for patients who developed the T790M resistance mutation following treatment with previous generation TKIs. Here, we report eleven patients who were treated by an increasing dose of osimertinib from 80 mg to 160 mg QD orally following intracranial progression in either 1 st or 2 nd line setting. Methods This is a sub-cohort analysis from a larger non-randomized, phase 2, open-label trial, evaluating the efficacy of osimertinib dose escalation from 80 to 160mg in EGFR mutated advanced NSCLC patients with intracranial progression in either 1 st (Arm A) or 2 nd line setting (Arm B for T790M+ and C for T790M-). Results Eleven patients, five in arm A, four in arm B and two in arm C were reported in this study. The mPFS of osimertinib before dose escalation was 11.4±8.9(6.6-30.7) months for arm A, 8.7±1.8(6.3-11.2) for arm B, and 14.5±7.8(6.7-22.3) for arm C. Intracranial response rate to dose-escalation was 54%(6/11) with 2/11 having intracranial stability. Median iPFS was 4.3±7.4(0.7-25.5) months; 3.8±6.4(1.8-18.9), 5.6±9.7(0.7-25.5) and 7.0±2.7(4.3-9.6) for arms A/B/C respectively. Dose escalation was well tolerated with diarrhea and paronychia as the main dose limiting symptoms. Conclusions Osimertinib 160 mg is feasible and may offer a therapeutic alternative for patients with isolated intracranial progression on osimertinib standard (80mg) dose. Further studies on CNS osimertinib pharmacokinetics are needed to test this hypothesis.

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 77 years (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 9.5 months (95% CI, 4.7–14.3), whereas it was 10.6 months (95% CI, 5.5–15.7) in first-line and 9.1 months (95% CI, 3.1–15.1) in pretreated patients. After a median follow-up of 11.0 months, 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.

Systemic capillary leak syndrome (SCLS) is a life-threatening disease. It is characterized by severe capillary hyperpermeability to proteins resulting in hemoconcentration, hypoalbuminemia and hypovolemic shock. Its treatment remains supportive, and the prognosis is generally poor. We report on a 51-year old male with melanoma treated with nivolumab for 1 year. 1 month following the completion of the treatment, the patient presented with signs of hypovolemic shock, anasarca, hemoconcentration and hypoalbuminemia. After excluding other diseases, a diagnosis of nivolumab-induced systemic capillary leak syndrome was made. A high dose of intravenous steroid therapy was promptly initiated without any significant clinical improvement. Intravenous immunoglobulin therapy was then administered with normalization of blood pressure, hemoconcentration and complete resolution of anasarca. Intravenous immunoglobulin should be considered a first-line treatment option for this rare phenomenon.

In the present case report, we aimed to describe 2 cases of myocarditis occurring as serious adverse effects of immune checkpoint inhibitors (ICIs) administered as treatment for metastatic melanoma. We describe 2 female patients: an 81-year-old treated with pembrolizumab and a 55-year-old treated with a combination of nivolumab and ipilimumab. Both patients underwent resection of metastases; while under treatment, both developed myocarditis, most probably as a toxicity from pembrolizumab and nivolumab plus Ipilimumab, respectively. While they achieved complete response, the occurrence of myocarditis as a toxicity of ICIs may have been a predictive sign that the immune system was sufficiently activated by the checkpoint inhibitor therapy to induce complete remission.

No abstract

<b><i>Introduction:</i></b> Non-small cell lung cancer (NSCLC) accounts for most lung cancers and is a leading cause of cancer-related deaths in the USA. Alterations in c-MET, a tyrosine kinase receptor, have been involved in many cases of NSCLC progression and metastasis. Crizotinib and other tyrosine kinase inhibitors (TKIs) have been used in NSCLC treatment with limited success. <b><i>Methods:</i></b> In this retrospective observational study, we analyzed data from patients diagnosed with lung cancer at Soroka University Medical Center between January 2015 and January 2020. We investigated patient characteristics, including disease-associated mutation type and median survival in response to different TKI treatments. <b><i>Results:</i></b> A total of 780 patients with lung cancer were included in the study, 134 of whom had small cell lung cancer and 646 had NSCLC. Of the NSCLC patients, 403 were diagnosed with advanced or metastatic disease, and 374 underwent molecular testing. We identified 16 patients with either c-MET mutations or amplifications who were treated with crizotinib. Of these patients, 7 expressed a c-MET exon 14 skipping mutation while the remaining 9 patients expressed c-MET amplification. Among the patients with a c-MET exon 14 skip mutation, the overall survival was 22.8 months and the median progression-free survival (PFS) on crizotinib treatment was 12.4 months. Of the patients with c-MET amplification, the median overall survival was 5.4 months and the median PFS with crizotinib treatment was 2.6 months. <b><i>Discussion and Conclusions:</i></b> We analyzed the data of a series of cases describing patients diagnosed with different stages of NSCLC, having either a c-MET exon 14 skipping mutation or an amplification mutation, and treated with various TKIs, including crizotinib. We investigated the characteristics of these patient groups in accordance with mutation types and compared median survival between patient groups. Crizotinib was found to be an optimal treatment for NSCLC harboring c-MET exon 14 skipping mutations.

Background Osimertinib is selective for both EGFR-TKI sensitizing and Thr790Met mutations. While intracranial activity of osimertinib is documented in larger trials, a prospective study focusing exclusively on patients with asymptomatic brain metastases has not been reported. Methods In this nonrandomized, phase II, open label, 3-arm prospective proof-of-concept pilot study, 48 patients with metastatic EGFR-mutant lung adenocarcinoma (LUAD) received osimertinib 80 mg daily. Patients were either treatment naïve (arm A=20) or previously treated with an EGFR-TKI and Thr790Met-positive (arm B=18) or negative (arm C=10). In cases of isolated intracranial progression, osimertinib dose was escalated (160 mg). The primary endpoints were intracranial objective response rate (iORR) and intracranial disease control rate (iDCR). The secondary endpoint was intracranial progression free survival (iPFS). This study is registered at Clinicaltrials.gov, NCT02736513. Results The iORR’s were 84.2%, 66.7% and 50% and the iDCR’s were 94.7%, 94.4% and 80% in arms A, B and C, respectively. The median iPFS was 11.8 months (95% CI 7.7-NA), 7.6 (95% CI 5.3-NA) and 6.3 months (95% CI 3.9-NA) in arms A, B and C, respectively. Following dose escalation, pooled iORR was 54% (arm A=5, arm B=4, arm C=2). Adverse events were similar to those in previously published literature. Conclusion Osimertinib demonstrated high efficacy on brain metastases. All trial arms displayed a significant decrease in the number and diameter of target lesions. These findings indicate that osimertinib is effective for Thr790Met-positive and negative LUAD patients with asymptomatic brain metastases. Therefore, osimertinib should be considered a viable option for EGFR-mutant patients with brain involvement regardless of their Thr790Met mutation status.