Andrew J. Plodkowski

Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial

SUMMARY Background RET rearrangements are found in 1–2% of non-small cell lung cancers. Cabozantinib is a multikinase RET inhibitor that produced a 10% response rate in unselected patients with lung cancers. To evaluate the activity of cabozantinib in patients with RET-rearranged lung cancers, we conducted a prospective phase 2 trial in this molecular subgroup. Methods We enrolled patients in this open-label, Simon two-stage, phase 2 trial if they met the following criteria: metastatic or unresectable lung cancer harboring a RET rearrangement, Karnofsky performance status of >70%, and measurable disease. Cabozantinib was administered at 60 mg daily. The primary objective was to determine the overall response rate (RECIST v1·1). This analysis was performed in an intent to treat fashion in patients who received at least one dose of cabozantinib and underwent imaging performed at baseline and at least one protocol-specified follow up time point. The secondary objectives were to determine progression-free survival, overall survival, and toxicity. The accrual of RET-rearranged lung cancer patients to this protocol has been completed. This study was registered with ClinicalTrials.gov, number NCT01639508. Findings Twenty six patients with RET-rearranged lung adenocarcinomas were treated with cabozantinib. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint with confirmed partial responses observed in seven of 25 response-evaluable patients (overall response rate 28% [95% CI 12–49%]). The most common grade 3 treatment-related adverse events were asymptomatic lipase elevation in four patients (15%), increased alanine aminotransferase in two patients (8%), increased aspartate aminotransferase in two patients (8%), thrombocytopenia in two patients (8%), and hypophosphatemia in two patients (8%). No drug-related deaths were observed. Nineteen patients (73%) required dose reduction due to drug-related adverse events. Interpretation The observed activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumor biology and novel therapeutic approaches will be required to improve outcomes with RET-directed targeted therapy.BACKGROUND RET rearrangements are found in 1-2% of non-small-cell lung cancers. Cabozantinib is a multikinase inhibitor with activity against RET that produced a 10% overall response in unselected patients with lung cancers. To assess the activity of cabozantinib in patients with RET-rearranged lung cancers, we did a prospective phase 2 trial in this molecular subgroup. METHODS We enrolled patients in this open-label, Simon two-stage, single-centre, phase 2, single-arm trial in the USA if they met the following criteria: metastatic or unresectable lung cancer harbouring a RET rearrangement, Karnofsky performance status higher than 70, and measurable disease. Patients were given 60 mg of cabozantinib orally per day. The primary objective was to determine the overall response (Response Criteria Evaluation in Solid Tumors version 1.1) in assessable patients; those who received at least one dose of cabozantinib, and had been given CT imaging at baseline and at least one protocol-specified follow-up timepoint. We did safety analyses in the modified intention-to-treat population who received at least one dose of cabozantinib. The accrual of patients with RET-rearranged lung cancer to this protocol has been completed but the trial is still ongoing because several patients remain on active treatment. This study was registered with ClinicalTrials.gov, number NCT01639508. FINDINGS Between July 13, 2012, and April 30, 2016, 26 patients with RET-rearranged lung adenocarcinomas were enrolled and given cabozantinib; 25 patients were assessable for a response. KIF5B-RET was the predominant fusion type identified in 16 (62%) patients. The study met its primary endpoint, with confirmed partial responses seen in seven of 25 response-assessable patients (overall response 28%, 95% CI 12-49). Of the 26 patients given cabozantinib, the most common grade 3 treatment-related adverse events were lipase elevation in four (15%) patients, increased alanine aminotransferase in two (8%) patients, increased aspartate aminotransferase in two (8%) patients, decreased platelet count in two (8%) patients, and hypophosphataemia in two (8%) patients. No drug-related deaths were recorded but 16 (62%) patients died during the course of follow-up. 19 (73%) patients required dose reductions due to drug-related adverse events. INTERPRETATION The reported activity of cabozantinib in patients with RET-rearranged lung cancers defines RET rearrangements as actionable drivers in patients with lung cancers. An improved understanding of tumour biology and novel therapeutic approaches will be needed to improve outcomes with RET-directed targeted treatment. FUNDING Exelixis, National Institutes of Health and National Cancer Institute Cancer Center Support Grant P30 CA008748.

Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing.

Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number-altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome sequencing (WES) was performed for 49 patients to compare quantification of TMB by targeted NGS versus WES. Results Estimates of TMB by targeted NGS correlated well with WES (ρ = 0.86; P < .001). TMB was greater in patients with DCB than with NDB ( P = .006). DCB was more common, and progression-free survival was longer in patients at increasing thresholds above versus below the 50th percentile of TMB (38.6% v 25.1%; P < .001; hazard ratio, 1.38; P = .024). The fraction of copy number-altered genome was highest in those with NDB. Variants in EGFR and STK11 associated with a lack of benefit. TMB and PD-L1 expression were independent variables, and a composite of TMB plus PD-L1 further enriched for benefit to ICIs. Conclusion Targeted NGS accurately estimates TMB and elevated TMB further improved likelihood of benefit to ICIs. TMB did not correlate with PD-L1 expression; both variables had similar predictive capacity. The incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.

Lamellated Hyperintense Synovitis: Potential MR Imaging Sign of an Infected Knee Arthroplasty

PURPOSE To determine the sensitivity and specificity of lamellated hyperintense synovitis for infection following knee arthroplasty and to determine the inter- and intraobserver variability of this sign at magnetic resonance (MR) imaging. MATERIALS AND METHODS The purpose of the retrospective case control study was approved by the hospitals institutional review board. MR images from 28 patients with proved infected total knee arthroplasty and 28 patients with noninfected arthroplasty were reviewed by two musculoskeletal radiologists for the presence of lamellated hyperintense synovitis. Cases were rereviewed 2 weeks later by each reader. The sensitivity and specificity were calculated with the initial reads. The κ statistic was used to assess inter- and intraobserver reliability. RESULTS The sensitivity of lamellated hyperintense synovitis for infection was 0.86-0.92 (95% confidence interval [CI]: 0.75, 0.97) and the specificity was 0.85-0.87 (95% CI: 0.74, 0.94). There was almost perfect interobserver agreement (κ = 0.82; 95% CI: 0.72, 0.93; P < .001) and intraobserver agreement (for reader 1, κ = 0.89 [95% CI: 0.78, 1.00; P < .001] and for reader 2, κ = 0.89 [95% CI: 0.77, 1.00; P < .001]) in the classification of the synovial pattern. CONCLUSION In this selected series of patients, the presence of lamellated hyperintense synovitis at MR imaging of knee arthroplasty had a high sensitivity and specificity for infection. This sign had high inter- and intraobserver reliability.

Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas.

Introduction: In patients with epidermal growth factor receptor (EGFR)-mutant or KRAS-mutant lung adenocarcinomas, the prognostic impact of a concurrent PIK3CA mutation remains unclear. Although preclinical data suggest that sensitivity to EGFR tyrosine kinase inhibition (TKI) is decreased in EGFR-mutant lung cancers also harboring a PIK3CA mutation, this interaction has not been explored clinically. Methods: Patients with lung adenocarcinomas harboring a PIK3CA mutation concurrent with a separate driver mutation were identified through mutational hotspot testing, multiplex sizing assays, and fluorescence in situ hybridization. Overall survival and outcomes with EGFR TKI monotherapy (EGFR-mutant) were estimated using Kaplan–Meier methods and compared between double-mutant (EGFR-mutant or KRAS-mutant, concurrent PIK3CA-mutant) and single-mutant patients (EGFR-mutant or KRAS-mutant, PIK3CA wild-type) using log-rank tests. Results: In EGFR-mutant and KRAS-mutant lung cancers, a concurrent PIK3CA mutation was associated with a decrease in median overall survival: 18 versus 33 months (EGFR double mutant, n = 10 versus single mutant, n = 43, p = 0.006), and 9 versus 16 months (KRAS double mutant, n = 16 versus single mutant, n = 47, p = 0.020). In EGFR-mutant lung cancers, a concurrent PIK3CA mutation did not impact benefit from EGFR TKI monotherapy. Single versus double mutant: objective response rate, 83% (n = 29) versus 62% (n = 6, p = 0.80); median time to progression, 11 (n = 29) versus 8 months (n = 6, p = 0.84); and median duration of TKI therapy, 15 (n = 32) versus 15 months (n = 10, p = 0.65). Conclusion: A concurrent PIK3CA mutation is a poor prognostic factor in patients with advanced EGFR-mutant or KRAS-mutant lung adenocarcinomas. There was no evidence that clinical benefit from EGFR TKI monotherapy is affected by a concurrent PIK3CA mutation in EGFR-mutant lung cancers.

Clinical outcomes with pemetrexed-based systemic therapies in RET-rearranged lung cancers

BACKGROUND RET rearrangements are targetable, oncogenic lung cancer drivers. While previous series have shown durable clinical benefit with pemetrexed-based therapies in ALK- and ROS1-rearranged lung cancers, the benefits of pemetrexed-based treatments in patients with RET-rearranged lung cancers relative to other genomic subsets have not previously been explored. PATIENTS AND METHODS A retrospective review of patients with pathologically confirmed stage IIIB/IV lung adenocarcinomas and evidence of a RET, ROS1, or ALK rearrangement, or a KRAS mutation was conducted. Patients were eligible if they received treatment with pemetrexed alone or in combination. The primary outcome of progression-free survival (PFS), and secondary outcomes of overall response rate (ORR, RECIST v1.1), time to progression (TTP), and time to treatment discontinuation were compared between RET-rearranged and groups of ROS1-rearranged, ALK-rearranged, and KRAS-mutant lung cancers. RESULTS We evaluated 104 patients. Patients with RET-rearranged lung cancers (n = 18) had a median PFS of 19 months [95% confidence interval (CI) 12-not reached (NR)] that was comparable with patients with ROS1- (23 months, 95% CI 14-NR, n = 10) and ALK-rearranged (19 months, 95% CI 15-36, n = 36) lung cancers, and significantly improved compared with patients with KRAS-mutant lung cancers (6 months, 95% CI 5-9, P < 0.001, n = 40). ORR (45%), median TTP (20 months, 95% CI 17-NR), and median time to treatment discontinuation (21 months, 95% CI 6-NR) in patients with RET-rearranged lung cancers were not significantly different compared with patients with ALK- and ROS1-rearranged lung cancers, and improved compared with patients with KRAS-mutant lung cancers. CONCLUSION Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma

KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) comutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P < 0.001) in the Stand Up To Cancer (SU2C) cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase III trial (0% vs. 57.1% vs. 18.2%; P = 0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P < 0.001) and overall (P = 0.0015) survival compared with KRASMUT;STK11/LKB1WT LUAC. Among 924 LUACs, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive non-small cell lung cancer. In Kras-mutant murine LUAC models, Stk11/Lkb1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC.Significance: This work identifies STK11/LKB1 alterations as the most prevalent genomic driver of primary resistance to PD-1 axis inhibitors in KRAS-mutant lung adenocarcinoma. Genomic profiling may enhance the predictive utility of PD-L1 expression and tumor mutation burden and facilitate establishment of personalized combination immunotherapy approaches for genomically defined LUAC subsets. Cancer Discov; 8(7); 822-35. ©2018 AACR.See related commentary by Etxeberria et al., p. 794This article is highlighted in the In This Issue feature, p. 781.

Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer

Background The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

Radiogenomic evaluation of lung cancer — Are there imaging characteristics associated with lung adenocarcinomas harboring BRAF mutations?

INTRODUCTION We studied computed tomography (CT) features associated with BRAF mutated lung cancer. MATERIALS AND METHODS CT features of BRAF mutated lung cancers were compared to stage matched lesions without BRAF mutation. RESULTS 47 (25%) patients with BRAF mutation and 141 (75%) without BRAF mutation were included. BRAF lesions were most frequently solid 37 (84%), spiculated 22 (50%), and peripheral 37 (84%). No feature of the primary tumor was significantly different between BRAF and non-BRAF groups. BRAF patients were more likely than KRAS patients to have pleural metastases [5 (11%) vs 0 (0%), p=0.045]. CONCLUSION No feature of the primary tumor differentiates BRAF lesions from non-BRAF lesions.

From genotype to phenotype: Are there imaging characteristics associated with lung adenocarcinomas harboring RET and ROS1 rearrangements?

INTRODUCTION Recurrent gene rearrangements are important drivers of oncogenesis in non-small cell lung cancers. RET and ROS1 rearrangements are each found in 1-2% of lung adenocarcinomas and represent distinct molecular subsets. This study assessed the computed tomography (CT) imaging features of patients with RET- and ROS1-rearranged lung cancers. METHODS Eligible patients included pathologically-confirmed lung adenocarcinomas of any stage with a RET or ROS1 rearrangement via fluorescence in-situ hybridization or next-generation sequencing, and available pre-treatment baseline imaging for review. A cohort of EGFR-mutant lung cancers was identified as a control group. CT features assessed included location, consistency, contour, presence of cavitation, and calcification of the primary tumor. Presence of an effusion, lung metastases, adenopathy and extrathoracic disease were recorded. The Wilcoxon rank-sum/Kruskal-Wallis and Fishers exact tests were used to compare features between groups. RESULTS 73 patients with lung adenocarcinomas were identified: 17 (23%) with ROS1 fusions, 25 (34%) with RET fusions and 31 (43%) with EGFR mutations. ROS1-rearranged lung cancers were more likely to present as peripheral tumors in comparison to EGFR-mutant lung cancers (32% vs. 65%, p=0.04). RET-rearranged lung cancers did not significantly differ from EGFR-mutant lung cancers radiographically. The consistency of the primary lesion for RET and ROS fusions and EGFR mutations were most frequently solid and spiculated. CONCLUSIONS Lung adenocarcinomas with RET and ROS1 fusions share many radiographic features and those with ROS1 fusions are more likely to present as peripheral lesions in comparison to EGFR-mutant lung cancers.

Preoperative Computed Tomography Findings Predict Surgical Resectability of Thymoma

Introduction: The aim of the study was to identify preoperative computed tomography (CT) imaging characteristics that correlated with surgical resectability. Methods: We retrospectively reviewed the CT scans of 133 patients who underwent surgical resection for thymoma at our institution between July 21, 1997, and September 22, 2010. Imaging characteristics recorded included tumor size, attenuation, contact of mediastinal vessels, tumor morphology, infiltration of surrounding fat, changes in the adjacent lung parenchyma, lymphadenopathy, and pleural involvement. Results: The study group included 66 men and 67 women, aged 23–88 years (mean 58.8 years). Eighty patients (60.2%) were Masaoka stage I or II and 53 (39.8%) were Masaoka stage III or IV. Twenty-three patients (17.3%) had an incomplete surgical resection. Of these, 15 patients had microscopic residual disease (11.2%) and eight had gross residual disease (6.0%). The preoperative CT characteristics that correlated with an incomplete surgical resection included a lobulated tumor contour (p = 0.016), greater than or equal 50% abutment of the circumference of an adjacent vessel (p < 0.001), thoracic lymphadenopathy (p = 0.029), adjacent lung changes (p = 0.005) and pleural nodularity (p = 0.001). Tumor size was larger in the incompletely versus completely resected groups, with mean values of 9.7 and 6.9 cm (p value 0.013). On multivariate analysis, only degree of abutment of adjacent vessels and pleural nodularity were independent predictors of incomplete resection. Conclusions: Preoperative CT findings can predict the likelihood of successful surgical resection and could help to identify patients who might benefit from neoadjuvant chemotherapy.