TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is an important molecular subgroup of tumors that are typically sensitive to tyrosine kinase inhibitors (TKIs). Although a substantial portion of patients benefit from TKIs, this approach is complicated by intrinsic and acquired resistance. We report a patient with ALK-rearranged NSCLC who showed an initial response to targeted therapy, but developed resistance to multiple TKIs. Serial comprehensive genomic profiling (CGP) was performed at four independent points during the clinical course. We review the pathology and clonal progression of the tumor, with CGP identifying a secondary CTNNB1 p.S45V mutation after the initiation of targeted therapy, followed by tertiary ALK p.I1171N. The presence of an alteration in a second oncogenic driver gene suggests a possible mechanism for resistance, and a secondary therapeutic target. Due to the involvement of Wnt signaling in the pathogenesis of many tumors and its association with immune evasion, a variety of therapeutic strategies are being developed to target this pathway. This case exemplifies the challenges of targeted therapeutics in the face of tumor progression, as well as the increasing role of genomics in understanding tumor biology.

Brigatinib in Patients With Alectinib-Refractory ALK-Positive NSCLC.

INTRODUCTION: The second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib recently showed superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has shown substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown. METHODS: A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes. RESULTS: Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 months). Among 9 patients in this study who underwent post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance mutation; of these, 1 had a confirmed partial response and 3 had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib. CONCLUSIONS: Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.

Stereotactic Body Radiation Therapy Boost After Concurrent Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer: A Phase 1 Dose Escalation Study.

PURPOSE: Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD). METHODS AND MATERIALS: Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (<120 cc and <60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients per cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated. RESULTS: Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at <24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P<.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively. CONCLUSIONS: SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24 Gy in 2 fractions. Toxicity at the PBV is a concern but potentially can be avoided with strict dose-volume constraints.

Outcomes after surgical resection of pulmonary carcinoid tumors.

BACKGROUND: Pulmonary carcinoid tumors make up approximately one percent of all pulmonary tumors, and controversy exists regarding management and prognosis. We undertook a retrospective analysis of all patients who underwent surgical resection of pulmonary carcinoid tumors at our institution. METHODS: From 1992 through 2014, 121 patients who underwent surgical resection of pulmonary carcinoid tumors were retrospectively reviewed. Patient demographics, pathologic data and long-term outcomes were recorded. RESULTS: There were 96 patients with typical carcinoid tumors and 25 patients with atypical carcinoid tumors. All patients received complete resection of their tumors, with 90 % (109/121) of patients undergoing anatomic resection. There were no peri-operative mortalities. Eighty-one percent (98/121) of patients were female. Mean age was 60.7 years. Five and ten year survival rates were 96 % and 88 % respectively for typical carcinoid tumors, as compared to 87 % and 69 % respectively for atypical carcinoid tumors. Tumor size was not associated with survival (p = 0.98). Nodal metastases were evident in 8 % (8/96) of typical carcinoid tumors and 28 % (7/25) percent of atypical carcinoid tumors. Among typical carcinoid cases, the presence of nodal metastases were not associated with overall survival (p = 0.55). Among atypical carcinoid cases, the presence of nodal metastases also was not associated with survival (p = 0.53). No patients received neoadjuvant or adjuvant chemoradiation treatment. CONCLUSIONS: Excellent long-term outcomes can be achieved following surgical resection of pulmonary carcinoid tumors. The presence of nodal metastases was not associated with overall survival. Tumor size was not associated with either recurrence rates or survival.