Purpose: Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting. Experimental Design: Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance. Results: Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial–mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors. Conclusions: This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.

Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach.

Several fibroblast growth factor receptor (FGFR) inhibitors are approved or in clinical development for the treatment of FGFR-driven urothelial cancer, and molecular mechanisms of resistance leading to patient relapses have not been fully explored. We identified 21 patients with FGFR-driven urothelial cancer treated with selective FGFR inhibitors and analyzed postprogression tissue and/or circulating tumor DNA (ctDNA). We detected single mutations in the FGFR tyrosine kinase domain in seven (33%) patients (FGFR3 N540K, V553L/M, V555L/M, E587Q; FGFR2 L551F) and multiple mutations in one (5%) case (FGFR3 N540K, V555L, and L608V). Using Ba/F3 cells, we defined their spectrum of resistance/sensitivity to multiple selective FGFR inhibitors. Eleven (52%) patients harbored alterations in the PI3K–mTOR pathway (n = 4 TSC1/2, n = 4 PIK3CA, n = 1 TSC1 and PIK3CA, n = 1 NF2, n = 1 PTEN). In patient-derived models, erdafitinib was synergistic with pictilisib in the presence of PIK3CA E545K, whereas erdafitinib–gefitinib combination was able to overcome bypass resistance mediated by EGFR activation. Significance: In the largest study on the topic thus far, we detected a high frequency of FGFR kinase domain mutations responsible for resistance to FGFR inhibitors in urothelial cancer. Off-target resistance mechanisms involved primarily the PI3K–mTOR pathway. Our findings provide preclinical evidence sustaining combinatorial treatment strategies to overcome bypass resistance. See related commentary by Tripathi et al., p. 1964. This article is featured in Selected Articles from This Issue, p. 1949

Purpose To evaluate the safety and efficacy of palliative treatment of patients with pathologic pelvic by using fluoroscopy and cone-beam CT needle guidance software to perform percutaneous fixation by internal cemented screw (FICS). Materials and Methods This single-center study involved retrospective analysis of 100 consecutive patients with cancer with pathologic pelvic fractures managed with percutaneous FICS. Image guidance was performed with fluoroscopy and cone-beam CT needle guidance software. Pain palliative outcomes and opioid use after FICS were compared by means of paired-sample t test. Results A total of 107 percutaneous FICS procedures were performed from 2010 to 2017 to palliate 141 pathologic fractures in 100 patients (mean age, 65.0 years ± 17.6 [standard deviation; female age, 66.3 years ± 18.0; mean, 63.7 years ± 17.2]). Of 107 procedures, 104 (97.2%) were technically successful, with mean postprocedure hospitalization of 2 days ± 3. Complications occurred in 14 patients: focal pain at procedure site for longer than 48 hours (n = 5), hematoma (n = 3), progressive fracture despite fixation (n = 2), infection (n = 1), tumor track seeding (n = 1), and screw displacement (n = 2). In the 88 patients who completed early follow-up, mean numeric rating scale pain score was significantly improved at 6 weeks from 6.1 ± 2.5 to 2.1 ± 3.0 (P < .001). Opioid use was reduced at 6 weeks (preprocedure vs postprocedure, 91.3 g ± 121 vs 64.6 g ± 124, respectively; P = .04). Conclusion Fluoroscopy and cone-beam CT–guided percutaneous fixation of pathologic pelvis fractures by internal cemented screw is a safe and effective approach that can reduce pain and opioid use. © RSNA, 2018

This review highlights the distinct imaging patterns associated with immunotherapy response and progression and considers novel imaging approaches to evaluate emerging immunotherapies. Criteria based on measurements of lesion diameter at CT have guided treatment with historical therapies due to the strong association between tumor size and survival. Clinical experience with immun...

For CT-guided percutaneous lung biopsy, positioning biopsy-side down, needle removal during expiration, autologous blood patch sealing, rapid rollover, and pleural patching, or PEARL, reduced pneum... Background Percutaneous CT-guided biopsy of lung nodules is an established method with high diagnostic accuracy but a high rate of pneumothorax and chest tube insertion compared with endobronchial ...