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Background: Lenvatinib and sorafenib are standard of care first-line treatments for advanced, radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC). However, most patients eventually become treatment-resistant and require additional therapies. The phase 3 COSMIC-311 study investigated cabozantinib in patients with RAIR DTC who progressed on lenvatinib, sorafenib, or both and showed that cabozantinib provided substantial clinical benefit. Presented in this study is an analysis of COSMIC-311 based on prior therapy and histology. Methods: Patients were randomized 2:1 (stratification: prior lenvatinib [yes/no]; age [≤65, >65 years]) to oral cabozantinib (60 mg tablet/day) or matched placebo. Eligible patients received 1-2 prior vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors for DTC (lenvatinib or sorafenib required), had a confirmed DTC diagnosis, and were refractory to or ineligible for radioiodine therapy. For this analysis, progression-free survival (PFS) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by a blinded independent radiology committee were evaluated by prior therapy (lenvatinib only, sorafenib only, both) and histology (papillary, follicular, oncocytic, poorly differentiated). Results: Two hundred fifty-eight patients were randomized (170 cabozantinib/88 placebo) who previously received sorafenib only ( n  = 96), lenvatinib only ( n  = 102), or both ( n  = 60). The median follow-up was 10.1 months. The median PFS (months) with cabozantinib/placebo was 16.6/3.2 (sorafenib only: hazard ratio [HR] 0.13 [95% confidence interval, CI, 0.06-0.26]), 5.8/1.9 (lenvatinib only: HR 0.28 [95% CI 0.16-0.48]), and 7.6/1.9 (both: HR 0.27 [95% CI 0.13-0.54]). The ORR with cabozantinib/placebo was 21%/0% (sorafenib only), 4%/0% (lenvatinib only), and 8%/0% (both). Disease histology consisted of 150 papillary and 113 follicular, including 43 oncocytic and 36 poorly differentiated. The median PFS (months) with cabozantinib/placebo was 9.2/1.9 (papillary: HR 0.27 [95% CI 0.17-0.43]), 11.2/2.5 (follicular: HR 0.18 [95% CI 0.10-0.31]), 11.2/2.5 (oncocytic: HR 0.06 [95% CI 0.02-0.21]), and 7.4/1.8 (poorly differentiated: HR 0.18 [95% CI 0.08-0.43]). The ORR with cabozantinib/placebo was 15%/0% (papillary), 8%/0% (follicular), 11%/0% (oncocytic), and 9%/0% (poorly differentiated). Safety outcomes evaluated were consistent with those previously observed for the overall population. Conclusions: Results indicate that cabozantinib benefits patients with RAIR DTC, regardless of prior lenvatinib or sorafenib treatments or histology. Clinical Trial Registration Number: NCT03690388.

Purpose: A precise oncologic approach for head and neck squamous cell carcinoma (HNSCC) is necessary. We performed a genomic profile-based umbrella trial for the patients with platinum-refractory recurrent and/or metastatic HNSCC., Methods: In this multicenter, open-label, single-arm phase II trial, we performed targeted next-generation sequencing (NGS). Patients were assigned to each treatment arm on the basis of their matching genomic profiles: arm 1, alpelisib, a PIK3CA inhibitor; arm 2, poziotinib, an epidermal growth factor receptor/HER2 inhibitor; arm 3, nintedanib, an fibroblast growth factor receptor inhibitor; and arm 4, abemaciclib, a CDK4/6 inhibitor. If there was no matching target, patients were allocated to arm 5, duvalumab ± tremelimumab, anti-PD-L1/cytotoxic T-cell lymphocyte-4 inhibitor. When progressive disease (PD) occurred in arms 1-4, cross over to arm 5 was allowed. The primary end point was disease control rate (DCR) in arm 1 and overall response rate (ORR) in arms 2-5 by investigator assessment., Results: Between October 2017 and August 2020, 203 patients were enrolled, including crossover. In arm 1, the ORR was 21.2% and DCR was 65.6%. The ORR was 0% for arm 2, 42.9% for arm 3, 0% for arm 4, and 15.6% for arm 5. In the case of PD with durvalumab, tremelimumab was added, and the ORR for durvalumab + tremelimumab was 2.2%. The median progression-free survival was 3.4, 3.2, 5.6, 1.6, and 1.7 months for each arm, respectively. The median overall survival was 12.4, 6.1, 11.1, 9.1, and 12.7 months, respectively. Overall, the toxicity profiles were manageable, and there were no treatment-related deaths., Conclusion: To our knowledge, this study is the first biomarker-driven umbrella trial for platinum-refractory HNSCC using matched molecular targeted agents. We found that NGS-based genomic phenotyping was methodologically feasible and applicable.

Background: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET -mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear., Methods: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety., Results: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively., Conclusions: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET -mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: This open-label, single-arm, phase II study evaluated the vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitor (TKI) rivoceranib in patients with recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC)., Patients and Methods: Eligible patients had confirmed disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) with ≥20% increase in radiologically or clinically measurable lesions or appearance of new lesions within the preceding 6 months. Patients received oral rivoceranib 700 mg once daily. Primary outcomes were objective response rate (ORR) by investigator review and by blinded independent review committee (BIRC)., Results: Eighty patients were enrolled and 72 were efficacy evaluable. Seventy-four patients had distant metastases and 49 received prior systemic treatment (14 received VEGFR TKIs). Per investigator and BIRC, respectively, ORR was 15.3% [95% confidence interval (95% CI), 7.9-25.7] and 9.7% (95% CI, 4.0-19.0); median duration of response was 14.9 months (95% CI, 4.9-17.3) and 7.2 months (95% CI, 3.5-8.4); and median progression-free survival was 9.0 months (95% CI, 7.3-11.5) and 9.0 months (95% CI, 7.7-11.5). Grade ≥3 treatment-related adverse events occurred in 56 patients (70.0%); the most common were hypertension (34, 42.5%) and stomatitis (6, 7.5%). Four grade 5 events occurred with one attributed to rivoceranib (epistaxis). Sixty-eight patients (85.0%) had ≥1 dose modifications and 16 patients (20.0%) discontinued rivoceranib for toxicity., Conclusions: In patients with progressing R/M ACC, rivoceranib demonstrated antitumor activity and a manageable safety profile consistent with other VEGFR TKIs., (©2023 The Authors; Published by the American Association for Cancer Research.)

We evaluated the safety, tolerability, pharmacokinetics and antitumor activity of barecetamab monotherapy and combination cetuximab therapy in patients with advanced solid cancers, especially head and neck cancer (HNC). Part 1 was a 3 + 3 dose-escalation study in which 15 patients received barecetamab at 1, 3, 5, 10 and 20 mg/kg intravenously (IV) on days 1 and 28 and weekly in patients with advanced solid cancer. Part 2 was a dose-expansion study including two patient groups with advanced HNC, including six patients receiving barecetamab at 20 mg/kg IV every 3 weeks and 12 patients receiving barecetamab and cetuximab (400 mg/m 2 on day 1 followed by 250 mg/m 2 every week). No dose-limiting toxicities (DLTs) were observed. Maximum serum target engagement was reached with trough levels of doses ≥3 mg/kg IV weekly. Common adverse drug reactions were diarrhea, stomatitis, dermatitis acneiform and decreased appetite. One durable complete response of more than 17 months was observed, and the overall response and disease control rates were 36.4% (4/11) and 81.1% (9/11), respectively, in the combination therapy group. In conclusion, DLT was not observed in barecetamab at 1 to 20 mg/kg. The recommended phase II dose was determined to be 20 mg/kg triweekly. Barecetamab and in cetuximab combination was well tolerated and demonstrated meaningful antitumor effects., (© 2023 UICC.)

Purpose: CB-103 selectively inhibits the CSL-NICD (Notch intracellular domain) interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This dose-escalation/expansion study aimed to determine safety, pharmacokinetics, and preliminary antitumor activity., Experimental Design: Patients ≥18 years of age with selected advanced solid tumors [namely, adenoid cystic carcinoma (ACC)] and hematologic malignancies were eligible. CB-103 was dosed orally in cycles of 28 days at escalating doses until disease progression. Notch-activating mutations were required in a dose confirmatory cohort. Endpoints included dose-limiting toxicities (DLT), safety, tumor response, pharmacokinetics, and pharmacodynamics. Exploratory analyses focused on correlates of Notch and target gene expression., Results: Seventy-nine patients (64, 12 dose-escalation cohorts; 15, confirmatory cohort) enrolled with 54% receiving two or more lines of prior therapy. ACC was the dominant tumor type (40, 51%). Two DLTs were observed [elevated gamma-glutamyl transferase (GGT), visual change]; recommended phase II dose was declared as 500 mg twice daily (5 days on, 2 days off weekly). Grade 3-4 treatment-related adverse events occurred in 15 patients (19%), including elevated liver function tests (LFTs), anemia, and visual changes. Five (6%) discontinued drug for toxicity; with no drug-related deaths. There were no objective responses, but 37 (49%) had stable disease; including 23 of 40 (58%) patients with ACC. In the ACC cohort, median progression-free survival was 2.5 months [95% confidence interval (CI), 1.5-3.7] and median overall survival was 18.4 months (95% CI, 6.3-not reached)., Conclusions: CB-103 had a manageable safety profile and biological activity but limited clinical antitumor activity as monotherapy in this first-in-human study., Significance: CB-103 is a novel oral pan-Notch inhibitor that selectively blocks the CSL-NICD interaction leading to transcriptional downregulation of oncogenic Notch pathway activation. This first-in-human dose-escalation and -confirmation study aimed to determine the safety, pharmacokinetics, and preliminary antitumor efficacy of CB-103. We observed a favorable safety profile with good tolerability and biological activity but limited clinical single-agent antitumor activity. Some disease stabilization was observed among an aggressive NOTCH-mutant ACC type-I subgroup where prognosis is poor and therapies are critically needed. Peripheral downregulation of select Notch target gene levels was observed with escalating doses. Future studies exploring CB-103 should enrich for patients with NOTCH-mutant ACC and investigate rational combinatorial approaches in tumors where there is limited success with investigational or approved drugs., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Background: At an interim analysis (median follow-up, 6.2 months; n = 187), the phase 3 COSMIC-311 trial met the primary end point of progression-free survival (PFS): cabozantinib improved PFS versus a placebo (median, not reached vs. 1.9 months; p < .0001) in patients with previously treated radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). The results from an exploratory analysis using an extended datacut are presented., Methods: Patients 16 years old or older with RAIR-DTC who progressed on prior lenvatinib and/or sorafenib were randomized 2:1 to oral cabozantinib tablets (60 mg/day) or a placebo. Placebo patients could cross over to open-label cabozantinib upon radiographic disease progression. The objective response rate (ORR) in the first 100 randomized patients and the PFS in the intent-to-treat population, both according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent review, were the primary end points., Results: At the data cutoff (February 8, 2021), 258 patients had been randomized (cabozantinib, n = 170; placebo, n = 88); the median follow-up was 10.1 months. The median PFS was 11.0 months (96% confidence interval [CI], 7.4-13.8 months) for cabozantinib and 1.9 months (96% CI, 1.9-3.7 months) for the placebo (hazard ratio, 0.22; 96% CI, 0.15-0.32; p < .0001). The ORR was 11.0% (95% CI, 6.9%-16.9%) versus 0% (95% CI, 0.0%-4.1%) (p = .0003) with one complete response with cabozantinib. Forty placebo patients crossed over to open-label cabozantinib. Grade 3/4 treatment-emergent adverse events occurred in 62% and 28% of the cabozantinib- and placebo-treated patients, respectively; the most common were hypertension (12% vs. 2%), palmar-plantar erythrodysesthesia (10% vs. 0%), and fatigue (9% vs. 0%). There were no grade 5 treatment-related events., Conclusions: At extended follow-up, cabozantinib maintained superior efficacy over a placebo in patients with previously treated RAIR-DTC with no new safety signals., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC. Methods: In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics. Results: At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm ( n  = 123) and the 140 mg/day capsules arm ( n  = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90-1.70; p  = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points. Conclusions: PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs. Clinical Trial Registry: ClinicalTrials.gov NCT01896479.

Gini's mean difference (GMD, mean absolute difference between any two distinct quantities) of the restricted mean survival times (RMSTs, expectation of life at a given time limit) has been proposed as a new metric where higher GMD indicates better prognostic value. GMD is applied to the RMSTs at 25 years time-horizon to evaluate the long-term overall survival of women with breast cancer who received neoadjuvant chemotherapy, comparing a classification based on the number (pN) versus a classification based on the ratio (LNRc) of positive nodes found at axillary surgery. A total of 233 patients treated in 1980-2009 with documented number of positive nodes (npos) and number of nodes examined (ntot) were identified. The numbers were categorized into pN0, npos = 0; pN1, npos = [1,3]; pN2, npos = [4,9]; pN3, npos ≥ 10. The ratios npnx = npos/ntot were categorized into Lnr0, npnx = 0; Lnr1, npnx = (0,0.20]; Lnr2, npnx = (0.20,0.65]; Lnr3, npnx > 0.65. The GMD for pN-classification was 5.5 (standard error: ± 0.9) years, not much improved over a simple node-negative vs. node-positive that showed a GMD of 5.0 (± 1.4) years. The GMD for LNRc-classification was larger, 6.7 (± 0.8) years. Among other conventional metrics, Cox-model LNRc's c-index was 0.668 vs. pN's c = 0.641, indicating commensurate superiority of LNRc-classification. The usability of GMD-RMSTs warrants further investigation., (© 2022. The Author(s).)

Introduction IMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 (programmed death-ligand 1). This study evaluated the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Materials and Methods This open-labeled phase I study used a standard 3 + 3 dose-escalation design, with doses ranging from 2 to 20 mg/kg. IMC-001 was administered intravenously every 2 weeks until disease progression or unacceptable toxicity. The dose-limiting toxicity window was defined as 21 days from the first dose. Results Fifteen subjects were included in 5 dose-escalation cohorts. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common adverse events (AEs) were general weakness, decreased appetite, fever, and cough. No grade 4 or 5 treatment emergent AEs were reported during the study. One subject in the 2 mg/kg cohort showed grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001. Over the dose range of 2-20 mg/kg IMC-001, the AUC 0-14d , AUC 0-∞ , and C max generally increased in a dose-proportional manner for each step of dose escalation. Of the 15 enrolled patients, 1 subject with rectal cancer showed a partial response, and the disease control rate was 33.3%. Conclusions IMC-001 demonstrated a favorable safety profile up to 20 mg/kg administered intravenously every 2 weeks and showed preliminary efficacy in patients with advanced solid tumors. Based on pharmacokinetic and pharmacodynamic data, 20 mg/kg was selected as the recommended phase II dose. Clinical trial identification NCT03644056 (date of registration: August 23, 2018)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Oncogenic alterations in RET represent important therapeutic targets in thyroid cancer. We aimed to assess the safety and antitumour activity of pralsetinib, a highly potent, selective RET inhibitor, in patients with RET-altered thyroid cancers., Methods: ARROW, a phase 1/2, open-label study done in 13 countries across 71 sites in community and hospital settings, enrolled patients 18 years or older with RET-altered locally advanced or metastatic solid tumours, including RET-mutant medullary thyroid and RET fusion-positive thyroid cancers, and an Eastern Co-operative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment). Phase 2 primary endpoints assessed for patients who received 400 mg once-daily oral pralsetinib until disease progression, intolerance, withdrawal of consent, or investigator decision, were overall response rate (Response Evaluation Criteria in Solid Tumours version 1.1; masked independent central review) and safety. Tumour response was assessed for patients with RET-mutant medullary thyroid cancer who had received previous cabozantinib or vandetanib, or both, or were ineligible for standard therapy and patients with previously treated RET fusion-positive thyroid cancer; safety was assessed for all patients with RET-altered thyroid cancer. This ongoing study is registered with clinicaltrials.gov, NCT03037385, and enrolment of patients with RET fusion-positive thyroid cancer was ongoing at the time of this interim analysis., Findings: Between Mar 17, 2017, and May 22, 2020, 122 patients with RET-mutant medullary and 20 with RET fusion-positive thyroid cancers were enrolled. Among patients with baseline measurable disease who received pralsetinib by July 11, 2019 (enrolment cutoff for efficacy analysis), overall response rates were 15 (71%) of 21 (95% CI 48-89) in patients with treatment-naive RET-mutant medullary thyroid cancer and 33 (60%) of 55 (95% CI 46-73) in patients who had previously received cabozantinib or vandetanib, or both, and eight (89%) of nine (95% CI 52-100) in patients with RET fusion-positive thyroid cancer (all responses confirmed for each group). Common (≥10%) grade 3 and above treatment-related adverse events among patients with RET-altered thyroid cancer enrolled by May 22, 2020, were hypertension (24 patients [17%] of 142), neutropenia (19 [13%]), lymphopenia (17 [12%]), and anaemia (14 [10%]). Serious treatment-related adverse events were reported in 21 patients (15%), the most frequent (≥2%) of which was pneumonitis (five patients [4%]). Five patients [4%] discontinued owing to treatment-related events. One (1%) patient died owing to a treatment-related adverse event., Interpretation: Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer., Funding: Blueprint Medicines., Competing Interests: Declaration of interests VS reports grants from Blueprint Medicines and LOXO Oncology–Eli Lilly; research funding or grant support from Roche–Genentech, Novartis, Bayer, GlaxoSmithKline (GSK), Nanocarrier, Vegenics, Northwest Biotherapeutics, Berg Heath, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Medimmune, Altum, Dragonfly Therapeutics, Takeda, Immunogen, National Comprehensive Cancer Network (NCCN), NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, and Boston Pharmaceuticals, travel support from Novartis, PharmaMar, ASCO, ESMO, Helsinn, and Incyte, and consultancy or advisory board participation for Helsinn, LOXO Oncology–Eli Lilly, R-Pharma US, Incyte, QED Pharma, Medimmune, and Novartis, and another relationship with Medscape. MIH reports advisory board roles for Eli Lilly, LOXO Oncology, and Blueprint Medicines, and research funding from Eli Lilly. LJW reports personal fees and other support from Blueprint Medicines; personal fees from Bayer, Blueprint Medicines, Exelixis, Genentech, Eli Lilly, and Merck, and non-financial support from Eli Lilly and Merck. MS reports grants from AstraZeneca and Bristol-Myers Squibb (BMS), and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, GSK, Janssen, MorphoSys, Novartis, Roche, Takeda, Amgen, and MSD. ASM reports consulting or advisory board roles (with honoraria to his institution) for Janssen, Genentech, BMS, AbbVie, AstraZeneca, travel or accommodation or expenses from AbbVie and Roche, and research funding from Novartis, NIH, Mark Foundation, and is a non-remunerated board member of the Mesothelioma Applied Research Foundation. GC reports personal fees from Roche, Pfizer, Novartis, Eli Lilly, Foundation Medicine, BMS, Samsung, AstraZeneca, Daiichi Sankyo, Boehringer Ingelheim, GSK, and Seagen, non-financial support from Roche and Pfizer, grants from Merck, and other support from Ellipses Pharma. MSB has nothing to disclose. VWZ reports personal fees from AstraZeneca, Blueprint Medicines, Roche-Foundation Medicine, Roche–Genentech, Takeda, Turning Point Therapeutics, and Xcovery. SL reports personal fees from Eisai and Eli Lilly. DWB reports personal fees from Blueprint Medicines. CSB reports grants from Blueprint Medicines, Daiichi Sankyo, Celgene, Pfizer, Lilly Oncology, AbbVie, Rain Therapeutics, Spectrum Pharmaceuticals, and personal fees from AstraZeneca, Turning Point Therapeutics, NCCN, and Takeda. DA reports grants and personal fees from Blueprint Medicines; grants from Exelixis, Kura Oncology, Merck, Cue, Aduro, Eli Lilly, Pfizer, Celgene–BMS, Novartis, AstraZeneca, Atara Bio, Cellex, Innate, Sensei, Matrix Biomed, Hookipa, CoFactor, Medimmune, and ISA, and personal fees from Exelixis, Merck, Cue, twoXAR, Vaccinex, Zilio, and TargImmune. BK has nothing to disclose. IM reports grants from an ESMO Research Fellowship sponsored by Roche, and personal fees for speaker bureau participation from MSD. EG reports personal fees from Genentech, Hoffman–LaRoche, Ellipses Pharma, Neomed Therapeutics, Boehringer Ingelheim, Janssen, Seattle Genetics, TFS, Alkermes, ThermoFisher, BMS, and MSD, grants from Menarini and Glycotope, and other support from Novartis, Roche, and ThermoFisher. JFG reports personal fees from BMS, Roche–Genentech, Merck, Takeda, LOXO Oncology–Lilly, Blueprint Medicines, Oncorus, Regeneron, Gilead, AstraZeneca, Pfizer, Novartis, and Moderna, grants from Takeda and Novartis, and institutional research support from BMS, LOXO Oncology–Lilly, Blueprint Medicines, Novartis, Moderna, Alexo, Tesaro, Jounce, Adaptimmune Therapeutics, and an immediate family member who is an employee of and holds equity in Ironwood Pharmaceuticals. GL reports other support from Bayer, Blueprint Medicines, Cue Biopharma, Eisai, Exelixis, Genentech, Eli Lilly, LOXO Oncology, Merck, and Rakuten Medical. C-CL reports personal fees from BeiGene, Blueprint Medicines, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eli Lilly, Novartis, Takeda, and Roche. YG has nothing to disclose. DS reports grants from Blueprint Medicines, personal fees from MSD, Eisai, Ipsen, Bayer, AstraZeneca, Surface Oncology, and non-financial support from Eisai, Ipsen, and Monia Therapeutics. SGM, CC, and HZ are employees of and hold equity interest in Blueprint Medicines. CDT is a former employee of and holds equity interest in Blueprint Medicines. MHT reports other support from Bayer, Blueprint Medicines, Novartis, Sanofi–Genzyme, ArQule, BMS, Eisai, Merck, Array BioPharma, LOXO Oncology, Abreos Biosciences, and Arch Oncology., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

ASP5878 is a selective small-molecule inhibitor of fibroblast growth factor receptors (FGFRs). This study investigated safety, tolerability, and antitumor effect of single and multiple oral doses of ASP5878 in patients with solid tumors. This phase 1, open label, first-in-human study comprised dose-escalation and dose-expansion parts. Primary objectives of the dose-escalation part were to identify the dose-limiting toxicity (DLT), maximum tolerated dose, and recommended dose of ASP5878 for the dose-expansion part. Nine dose cohorts of ASP5878 were evaluated (0.5─2 mg once daily; 2─40 mg twice daily [BID]). A single dose of ASP5878 was followed by a 2-day pharmacokinetic collection, and then either 28-day cycles of daily dosing (ASP5878 ≤ 10 mg BID) or 5-day dosing/2-day interruption (ASP5878 ≥ 20 mg BID). The primary objective of the dose-expansion part was to determine the safety of ASP5878 (16 mg BID) administered in 28-day cycles of 5-day dosing/2-day interruption in patients with urothelial carcinoma, hepatocellular carcinoma, or squamous cell lung carcinoma with FGFR genetic alterations. Safety was assessed by monitoring adverse events (AEs). Thirty-five patients were enrolled and 31 discontinued in the dose-escalation part; 51 patients were enrolled and 51 discontinued in the dose-expansion part. In the dose-escalation part, 66.7% of patients in the 20 mg BID 5-day dosing/2-day interruption group reported DLTs of hyperphosphatemia. The recommended dose for the dose-expansion part was 16 mg BID. Common AEs included retinal detachment, diarrhea, and increased alanine aminotransferase. One death occurred that was not related to ASP5878. ASP5878 was well tolerated with manageable toxicities including hyperphosphatemia.

Background/aims: Although crizotinib is standard chemotherapy for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), clinical factors affecting progression-free survival (PFS) have not been reported. The purpose of this study was to identify clinical factors affecting PFS of crizotinib and develop a prognostic model for advanced ALK-positive NSCLC., Methods: Clinicopathologic features of patients enrolled in PROFILE 1001, 1005, 1007, and 1014 (training cohort) were reviewed. We conducted multivariate Cox analysis for PFS and overall survival (OS) in the training cohort (n = 159) and generated a proportional hazards model based on significant clinicopathologic factors, and then validated the model in an independent validation cohort (n = 40)., Results: In the training cohort, the objective response rate was 81.5%. Median PFS and OS from the start of crizotinib were 12.4 and 31.3 months, respectively. Multivariate Cox analysis showed poor performance status, number of metastatic organs (≥ 3), and no response to crizotinib independently associated shorter PFS. Based on a score derived from these three factors, median PFS and OS of patients with one or two factors were significantly shorter compared to those without these factors (median PFS, 22.4 months vs. 10.5 months vs. 6.5 months; median OS, not reached vs. 29.1 months vs. 11.8 months, respectively; p < 0.001 for each group). This model also had validated in an independent validation cohort., Conclusion: Performance status, number of metastatic organs, and response to crizotinib affected PFS of crizotinib in ALK-positive NSCLC. Based on these factors, we developed a simple and useful prediction model for PFS.

Pruritus is a very common symptom in patients, undergoing targeted anticancer therapy. However, the characteristics of pruritus, according to the targeted anticancer agents, are still unclear. The objective of this study was to determine the characteristics of pruritus, induced by targeted anticancer agents, using a questionnaire-based survey. The survey was administered to cancer patients currently receiving anticancer agents. Medical records were also reviewed. A total of 374 cancer patients completed the survey, of which 108 were treated with the targeted therapy. A total of 205 patients had pruritus, of which 66 were under the targeted therapy. Epidermal growth factor receptor inhibitor (EGFRI) users showed the highest prevalence rate of itching and numeric rating scale score for itching. The 5-D itch score was also highest among users of EGFRIs. In conclusion, patients receiving EGFRIs suffer from severe pruritus frequently. They not only experienced long lasting and intense itching, causing sleep discomfort, but also developed itching at specific body sites.

Purpose: Despite the successful use of tyrosine kinase inhibitors (TKIs) in cancer patients, their effect on herpes zoster development has not been studied. The aim of this study was to evaluate and compare the effects of epidermal growth factor receptor (EGFR) TKI and cytotoxic chemotherapy on the risk of herpes zoster development in non-small cell lung cancer (NSCLC) patients., Materials and Methods: We conducted a medical review of all eligible NSCLC patients in Seoul National University hospital between 2002 and 2015. We classified patients based on whether they previously underwent EGFR TKI therapy into either the TKI group or the cytotoxic group. We compared the incidence rates of herpes zoster during TKI therapy and cytotoxic chemotherapy. Additionally, the longitudinal risk of herpes zoster from TKIs was analyzed using the incidence rate ratio (IRR) of the TKI group to the cytotoxic group and the log-rank test of the Kaplan-Meier method., Results: Of the 2,981 NSCLC patients, 54 patients (1.54%) developed herpes zoster. In the TKI group (2,002 patients), the IRR of herpes zoster during TKI therapy compared to that during cytotoxic chemotherapy was 1.05 (95% confidence interval [CI], 0.53 to 2.09). The IRR of the TKI group compared to the cytotoxic group was 1.33 (95% CI, 0.64 to 2.76). The Kaplan-Meier cumulative risk of both groups was not significantly different., Conclusion: Our results show that the incidence rate of herpes zoster in the TKI group was not statistically different from the incidence in the cytotoxic group during and after chemotherapy in NSCLC patients.

Purpose: Patients treated with anticancer agents often experience a variety of treatment-related skin problems, which can impair their quality of life., Materials and Methods: In this cross-sectional study, Dermatology Life Quality Index (DLQI) and clinical information were evaluated in patients under active anticancer treatment using a questionnaire survey and their medical records review., Results: Of 375 evaluated subjects with anticancer therapy, 136 (36.27%) and 114 (30.40%) were treated for breast cancer and colorectal cancer, respectively. We found that women, breast cancer, targeted agent use, and longer duration of anticancer therapy were associated with higher dermatology-specific quality of life distraction. In addition, itching, dry skin, easy bruising, pigmentation, papulopustules on face, periungual inflammation, nail changes, and palmoplantar lesions were associated with significantly higher DLQI scores. Periungual inflammation and palmoplantar lesions scored the highest DLQI., Conclusion: We believe our findings can be helpful to clinicians in counseling and managing the patients undergoing anticancer therapy.

Standard treatment for locally advanced (stage III-IV) head and neck squamous cell cancer (LA-HNSCC) is concurrent chemoradiation therapy (CCRT) with cisplatin 100 mg/m every 3 weeks. For medically unfit patients susceptible to treatment-related adverse events, low-dose weekly cisplatin (30-40 mg/m) can be used as an alternative. In this study, we retrospectively compared the therapeutic outcomes of low-dose weekly cisplatin regimen and standard regimen in CCRT for LA-HNSCC.The medical records of histologically confirmed LA-HNSCC patients were retrospectively reviewed from January 1, 2007 to December 31, 2012. Patients who were treated with CCRT as initial treatment were included.Among 220 patients eligible, 65 (29.5%) were treated with cisplatin dosing schedule of 100 mg/m every 3 weeks and 155 (70.5%) with 30 to 40 mg/m weekly. The overall response rate in 3-weekly group was 92.3% and did not differ from that in weekly group (91.0%). The median progression-free survival of the weekly group was not attained but was not significantly different from that of 3-weekly group (50.7 months, 95% confidence interval [CI] 42.2-59.1 months) (P = .81). Also, the median overcall survival did not differ significantly between 2 groups (P = .34).In the present study, low-dose weekly cisplatin showed therapeutic outcomes comparable to standard-dose cisplatin in CCRT for LA-HNSCC. Prospective comparison of standard-dose three-weekly and low-dose weekly cisplatin is warranted.

Purpose: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC., Materials and Methods: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors., Results: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p<0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p<0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03-1.42; p=0.106)., Conclusion: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2018)

Objectives: To find predictors of non-diagnostic repeat biopsy specimen acquisition for mutational analysis and detection of epidermal growth factor receptor (EGFR) T790M mutation., Methods: We retrospectively reviewed 90 non-small cell lung cancer patients harbouring EGFR mutations who underwent repeat cone-beam CT-guided transthoracic needle biopsy. Clinical characteristics as well as biopsy-related factors were compared between patients with and without diagnostic specimen acquisition and between patients with and without T790M mutation. After univariate analysis, multivariate logistic regression analysis was performed to reveal independent predictors., Results: Diagnostic biopsy specimens for mutational test were obtained in 90% (81/90) of patients, of which 62% (50/81) possessed T790M mutation. None of the analysed variables were significantly associated with non-diagnostic specimen acquisition. For T790M detection, duration of EGFR tyrosine kinase inhibitor treatment (p = 0.066), duration of total chemotherapy (p = 0.026), tumour size (p = 0.066), and metastatic lung lesion as a biopsy target (p = 0.029) showed p values less than 0.10. Multivariate analysis revealed that target tumour size (odds ratio, 0.765; p = 0.031) was an independent predictor of T790M mutation. Metastatic lesions as biopsy targets (odds ratio, 4.194; p = 0.050) showed marginal statistical significance., Conclusions: Non-diagnostic repeat biopsy specimen acquisition was not related to the clinical or technical factors. However, detection of T790M at repeat biopsy might be associated with smaller target tumour size and selection of metastatic lesions as biopsy targets., Key Points: • Cone-beam CT-guided repeat biopsy yielded high diagnostic specimen acquisition rate. • Biopsy-related features were associated with the detection of T790M mutation. • Target tumour size was an independent predictor of the T790M detection. • Biopsy targeting metastatic lung nodules might help detect the T790M mutation.

Intratumoral heterogeneity has been suggested to be an important resistance mechanism leading to treatment failure. We hypothesized that radiologic images could be an alternative method for identification of tumor heterogeneity. We tested heterogeneity textural parameters on pretreatment FDG-PET/CT in order to assess the predictive value of target therapy. Recurred or metastatic non-small cell lung cancer (NSCLC) subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory data set (n = 161) and a validation data set (n = 21) were evaluated, and eight parameters were selected for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and the predictive value was calculated using Harrell's C-index. Univariate analysis revealed that all eight parameters showed an increased hazard ratio (HR) for progression-free survival (PFS). The highest HR was 6.41 (P<0.01) with co-occurrence (Co) entropy. Increased risk remained present after adjusting for initial stage, performance status (PS), and metabolic volume (MV) (aHR: 4.86, P<0.01). Textural parameters were found to have an incremental predictive value of early EGFR tyrosine kinase inhibitor (TKI) failure compared to that of the base model of the stage and PS (C-index 0.596 vs. 0.662, P = 0.02, by Co entropy). Heterogeneity textural parameters acquired from pretreatment FDG-PET/CT are highly predictive factors for PFS of EGFR TKI in EGFR-mutated NSCLC patients. These parameters are easily applicable to the identification of a subpopulation at increased risk of early EGFR TKI failure. Correlation to genomic alteration should be determined in future studies.

Purpose: To determine if the radiomic features on CT can predict progression-free survival (PFS) in epidermal growth factor receptor (EGFR) mutant adenocarcinoma patients treated with first-line EGFR tyrosine kinase inhibitors (TKIs) and to identify the incremental value of radiomic features over conventional clinical factors in PFS prediction., Methods: In this institutional review board-approved retrospective study, pretreatment contrast-enhanced CT and first follow-up CT after initiation of TKIs were analyzed in 48 patients (M:F = 23:25; median age: 61 years). Radiomic features at baseline, at 1st first follow-up, and the percentage change between the two were determined. A Cox regression model was used to predict PFS with nonredundant radiomic features and clinical factors, respectively. The incremental value of radiomic features over the clinical factors in PFS prediction was also assessed by way of a concordance index., Results: Roundness (HR: 3.91; 95% CI: 1.72, 8.90; P = 0.001) and grey-level nonuniformity (HR: 3.60; 95% CI: 1.80, 7.18; P<0.001) were independent predictors of PFS. For clinical factors, patient age (HR: 2.11; 95% CI: 1.01, 4.39; P = 0.046), baseline tumor diameter (HR: 1.03; 95% CI: 1.01, 1.05; P = 0.002), and treatment response (HR: 0.46; 95% CI: 0.24, 0.87; P = 0.017) were independent predictors. The addition of radiomic features to clinical factors significantly improved predictive performance (concordance index; combined model = 0.77, clinical-only model = 0.69, P<0.001)., Conclusions: Radiomic features enable PFS estimation in EGFR mutant adenocarcinoma patients treated with first-line EGFR TKIs. Radiomic features combined with clinical factors provide significant improvement in prognostic performance compared with using only clinical factors.

Background: Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC., Methods: This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used., Results: The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events., Conclusions: Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background/aims: The predictive and prognostic value of KRAS mutation and its type of mutations in non-small cell lung cancer (NSCLC) are controversial. This clinical study was designed to investigate the predictive value of KRAS mutations and its mutation types to pemetrexed and gemcitabine based treatment., Methods: Advanced NSCLC patients tested for KRAS mutation (n = 334) were retrospectively reviewed and 252 patients with wild type epidermal growth factor receptor and no anaplastic lymphoma kinase fusion were enrolled for the analysis. KRAS mutations were observed in 45 subjects with mutation type as followed: G12C (n = 13), G12D (n = 12), G12V (n = 12), other (n = 8). Response rate (RR), progression-free survival (PFS), and overall survival (OS) of pemetrexed singlet and gemcitabine based chemotherapy were analysis., Results: Age, sex, performance status were well balanced between subjects with or without KRAS mutations. No difference was observed in RR. Hazard ratio (HR) of PFS for pemetrexed treated subjects with G12C mutation compared to subjects with KRAS wild type was 1.96 (95% confidential interval [CI], 1.01 to 3.79; p = 0.045), but other mutations failed to show clinical significance. By analysis done by PFS, compared to the subjects with transition mutation, HR was 1.48 (95% CI, 0.64 to 3.40; p = 0.360) for subjects with transversion mutation on pemetrexed treatment and 0.41 (95% CI, 0.19 to 0.87; p = 0.020) for subjects treated with gemcitabine based chemotherapy. No difference was observed in OS., Conclusions: In this study, different drug sensitivity was observed according to the type of KRAS mutation. NSCLC subpopulations with different KRAS mutation type should be considered as different subgroups and optimal chemotherapy regimens should be searched in further confirmative studies.

Background: Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and safety of vandetanib 300 mg daily in this patient population., Patients and Methods: This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0-2. The primary endpoint was the objective response rate., Results: A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35-71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity., Conclusion: Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background/aims: Pretreatment nutritional status is an important prognostic factor in patients treated with conventional cytotoxic chemotherapy. In the era of target therapies, its value is overlooked and has not been investigated. The aim of our study is to evaluate the value of nutritional status in targeted therapy., Methods: A total of 2012 patients with non-small cell lung cancer (NSCLC) were reviewed and 630 patients with activating epidermal growth factor receptor (EGFR) mutation treated with EGFR tyrosine kinase inhibitor (TKI) were enrolled for the final analysis. Anemia, body mass index (BMI), and prognostic nutritional index (PNI) were considered as nutritional factors. Hazard ratio (HR), progression-free survival (PFS) and overall survival (OS) for each group were calculated by Cox proportional analysis. In addition, scores were applied for each category and the sum of scores was used for survival analysis., Results: In univariable analysis, anemia (HR, 1.29; p = 0.015), BMI lower than 18.5 (HR, 1.98; p = 0.002), and PNI lower than 45 (HR, 1.57; p < 0.001) were poor prognostic factors for PFS. Among them, BMI and PNI were independent in multi-variable analysis. All of these were also significant prognostic values for OS. The higher the sum of scores, the poorer PFS and OS were observed., Conclusions: Pretreatment nutritional status is a prognostic marker in NSCLC patients treated with EGFR TKI. Hence, baseline nutritional status should be more carefully evaluated and adequate nutrition should be supplied to these patients., Competing Interests: No potential conflict of interest relevant to this article was reported.

Introduction: Therapies targeting programmed cell death-1 (PD-1) and its ligand (PD-L1) have been successful in a subset of patients with non-small-cell lung cancer (NSCLC). PD-L1 expression in tumor tissues has been suggested as a predictive and prognostic marker. We examined the change in PD-L1 expression after gefitinib in patients with EGFR-mutant NSCLC., Materials and Methods: Paired tumor tissues were collected before and after gefitinib from 18 patients. PD-L1 expression on the tumor and immune cells was defined by the H-score of immunohistochemical staining (range, 0-300). The correlations between the change in PD-L1 expression and clinicopathologic characteristics were analyzed., Results: PD-L1 expression on tumor cells showed an increase in the median H-score from 25 to 40 (P = .067). Of the 18 patients, 7 (38.9%) had a marked increase in the median H-score (range, 80-180; group A) and 11 (61.1%) had no change in the median H-score (0 for both scores; group B). In groups A and B, the median progression-free survival for gefitinib was 13 and 12 months (P = .594), and the median overall survival was "not reached" and 38 months (P = .073), respectively. MET positivity by immunohistochemistry in biopsies after gefitinib therapy was significantly associated with group A (P = .028). The PD-L1 H-score by immunohistochemistry, but not by tumor cells, showed correlations with other immune cells; FOXP3(+) expression in biopsies before gefitinib use, and PD-1(+) and CD3(+) in biopsies after gefitinib therapy, respectively., Conclusion: PD-L1 expression in tumor cells markedly increased in a subset of patients after gefitinib treatment. Thus, rebiopsy should be considered when using PD-L1 expression as a biomarker., (Copyright © 2015 Elsevier Inc. All rights reserved.)

EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy has achieved favorable clinical outcomes in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, patients eventually develop resistance to EGFR-TKIs by several mechanisms. Adenine nucleotide translocase-2 (ANT2) is an oncogenic mitochondrial membrane-associated protein. We investigated the therapeutic potential of ANT2 inhibition to EGFR-TKI resistance in NSCLC using gefitinib-sensitive (PC9 and HCC827) and gefitinib-resistant (H1975 and HCC827/GR) NSCLC cell lines. ANT2 was inhibited by transfecting cells with an ANT2-specific shRNA. ANT2 expression was elevated in the H1975 and HCC827/GR cells compared with the PC9 and HCC827 cells. ANT2 upregulation in gefitinib-resistant cells was associated with increased SP1 binding to the ANT2 promoter. ANT2-specific shRNA decreased NSCLC cell viability. Moreover, ANT2-specific shRNA sensitized the H1975 and HCC827/GR cells to gefitinib, accompanied by HSP90 and EGFR downregulation. ANT2-specific shRNA also inactivated the PI3K/Akt signaling pathway in the H1975 and HCC827/GR cells, which was mediated by the suppression of miR-221/222 levels and by the subsequent restoration of PTEN. In EGFR-TKI-treated NSCLC patients, ANT2 expression was higher in patients exhibiting poor responses compared with patients showing excellent responses. Furthermore, ANT2 expression increased in tumor tissues biopsied after acquiring gefitinib resistance compared with tissues before gefitinib treatment. These findings suggest that ANT2 overexpression contributes to EGFR-TKI resistance in NSCLC and that ANT2 targeting may be considered a novel strategy for overcoming this resistance. Mol Cancer Ther; 15(6); 1387-96. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: A low albumin-to-globulin ratio (AGR) has been known as a prognostic factor for cancer-related mortality. However, no study has elucidated its usefulness as a predictive factor in the era of targeted therapy, and so, we evaluated this in the present study., Methods: We retrospectively analyzed 2012 non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Among these patients, 645 patients who had EGFR mutation and suitable pretreatment laboratory values were included. AGR was calculated 2 months before treatment and 4 months after treatment in each patient. The optimal cutoff value of AGR, and progression free survival (PFS) were also determined., Results: The optimal cutoff value of AGR was 1.17, which yielded a highest HR of 1.89 (P< 0.001) for poor PFS. The median PFS was 9.5 months (95% confidential interval [CI] 7.0-10.4) in patients with pretreatment AGR < 1.17 and 13.5 months (95% CI 11.9-14.7) in those with pretreatment AGR ≥ 1.17. Pretreatment AGR showed an independent predictive value (adjusted HR 1.80, P < 0.001) when age, performance status, and pre-TKI systemic treatment was adjusted for., Conclusions: We suggest that patients with NSCLC with EGFR mutations who have AGR values lower than 1.17 at the beginning of EGFR TKI treatment should be considered to have a high risk of early EGFR TKI failure.

Purpose: Interstitial lung disease (ILD) is a serious adverse effect of gefitinib. We examined the incidence and clinical characteristics of drug-induced ILD in Korean non-small cell lung carcinoma patients treated with gefitinib., Materials and Methods: A retrospective cohort study was performed in non-small cell lung cancer (NSCLC) patients who started gefitinib treatment at Seoul National University Hospital from January 2002 through December 2011. Patients who developed new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as having possible adverse pulmonary reactions. The patients' medical records were reviewed independently by investigators to identify the causes of pulmonary toxicities., Results: Among the 1,114 patients evaluated, 128 patients (11.5%) developed pulmonary adverse reactions after taking gefitinib. An infectious complication occurred in 98 patients (8.8%) and 15 patients (1.3%) developed ILD. Nine of the 15 patients (60.0%) with gefitinib-induced ILD experienced a fatal clinical course that met either the Common Terminology Criteria for Adverse Events grade 4 (n=3) or grade 5 (n=6). In the multivariate analysis, a lower serum albumin level (≤ 3.0 g/dL) at baseline was significantly associated with the development of gefitinib-induced ILD (odds ratio, 3.91; 95% confidence interval, 1.20 to 12.71)., Conclusion: The incidence of gefitinib-induced ILD in Korean NSCLC patients was similar to that reported worldwide, but lower than values reported for Japanese population. ILD was usually a life-threatening adverse effect of gefitinib, and the development of ILD was significantly associated with a lower baseline serum albumin level.

The purpose of this study was to investigate the clinical activity, safety and predictive biomarkers of dacomitinib, an irreversible pan-HER inhibitor, in patients with recurrent or metastatic esophageal squamous cell carcinoma (R/M-ESCC). Patients, whose diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv 1.1. Predictive biomarker analyses included the characterization of somatic mutations and gene expression using the Ion Torrent AmpliSeq Cancer Hotspot Panel and Nanostring nCounter, and investigation of their relationship with clinical outcomes. Of the 48 evaluable patients, 6 (12.5%) achieved partial responses and 29 (60.4%) had stable disease. The median response duration was 7.1 months. The median progression free survival (PFS) and overall survival (OS) was 3.3 months (95% CI, 2.4-4.3 months) and 6.4 months (95% CI, 4.4-8.4 months). Adverse events were mostly grade 1-2. Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS ≥ 4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001). Upregulation of ERBB signaling pathway was significantly associated with longer PFS (5.0 vs. 2.9 months, P = 0.016) and OS (10.0 vs. 4.8 months, P = 0.022). The most frequent mutations were TP53 (61%) followed by CDKN2A (8%), MLH1 (8%), FLT3 (8%) and EGFR (8%). Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-ESCC. Screening of ERBB pathway-related gene expression profiles may help identify patients who are most likely benefit from dacomitinib.

Background: Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy., Methods: We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate., Results: Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus., Conclusions: Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Background/aims: The purpose of this study was to identify predictive factors for erlotinib treatment in non-small cell lung cancer (NSCLC) patients following gefitinib failure., Methods: Forty-five patients with NSCLC who were treated with erlotinib following gefitinib failure at Seoul National University Hospital between August 2005 and November 2011 were enrolled. Epidermal growth factor receptor (EGFR) mutation status, pathologic findings and other clinical factors, including response to tyrosine kinase inhibitors (TKIs) and progression-free survival (PFS), were evaluated., Results: Of the 45 patients, 40 patients (88.8%) had adenocarcinoma. The following EGFR mutations were observed: five patients with a deletion of exon 19, six patients with an L858R mutation, three patients with wild-type EGFR, and 31 patients with unknown mutations. The response rate of erlotinib was 4.4%, and stable disease was 42.2%. The median PFS for erlotinib was 2.6 months (95% confidence interval, 1.4 to 3.7). Patients with a PFS ≥ 4 months during previous gefitinib treatment had a significantly longer PFS with erlotinib (3.3 months vs. 1.6 months, respectively; p < 0.01) than patients with PFS < 4 months with gefitinib. According to multivariate analyses, PFS ≥ 4 months for previous gefitinib treatment was significantly associated with prolonged PFS with erlotinib (p = 0.04). However, the response rate of gefitinib and treatment sequence were not associated with prolonged PFS with erlotinib (p = 0.28 and p = 0.67, respectively)., Conclusions: Following rechallenge with the EGFR TKI erlotinib following gefitinib failure, patients who showed prolonged PFS with gefitinib benefit from erlotinib. However, further prospective studies are needed to confirm these findings.

Introduction: The purpose of this study was to evaluate the predictive role of quantitative metabolic parameters using total lesion glycolysis (TLG) in F-2-fluoro-2-deoxyglucose-positron emission tomography/computed tomography for developing gefitinib resistance in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients treated with first-line gefitinib., Methods: A total of 75 NSCLC patients harboring activating EGFR mutation and receiving first-line gefitinib were analyzed. Whole-body F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography scans were acquired before first-line gefitinib. The maximal standardized uptake value and TLG of all lesions were calculated. Maximal standardized uptake value and TLG were categorized using the tertile cutoff. Treatment outcomes were compared between groups., Results: Overall response rate of gefitinib was 69.4%, and median progression-free survival (PFS) of gefitinib was 11.5 months. Overall response rates were similar between low, intermediate, and high TLG groups (68.0% versus 76.0% versus 68.0%, p = 0.274). However, PFS significantly differed by TLG groups, and high TLG was associated with shorter PFS (7.2 months in high TLG; 11.9 months in intermediate TLG; and 24.2 months in low, p < 0.001). Multivariate models adjusted for disease status and response to gefitinib showed that TLG was an independent predictive factor for PFS. TLG was also significantly associated with overall survival (p = 0.005)., Conclusion: TLG can predict PFS and development of gefitinib resistance in EGFR-mutant NSCLC patients treated with first-line gefitinib. Baseline metabolic tumor burdens measured with TLG before first-line gefitinib will be of great help in predicting time to acquired resistance.

Background: The objective of this study was to evaluate the efficacy and safety of dovitinib in patients with adenoid cystic carcinoma (ACC)., Methods: ACC patients with documented disease progression within the past 12 months were eligible. Patients received oral dovitinib (500 mg once daily for 5 consecutive days followed by a 2-day rest every week) until disease progression or unacceptable toxicities. The primary endpoint was the probability of 4-month progression-free survival (PFS). Metabolic response was evaluated with positron emission tomography (PET)/computed tomography (CT) scans performed at the baseline and after 8 weeks of treatment., Results: Between September 2011 and April 2013, 32 patients with metastatic and/or unresectable ACC were enrolled in this prospective, multicenter trial. The 4-month PFS probability was 80.4%, and the median PFS was 6.0 months (95% confidence interval, 4.4-7.6 months). Tumor shrinkage was observed in 22 patients (68.8%), and 1 patient had a confirmed partial response. The disease control rate was 96.9%. Among 26 patients with PET/CT scans both before and after treatment (at 8 weeks), the metabolic activity of ACC was reduced in 13 patients (50.0%), and 5 patients (19.2%) achieved a metabolic partial response, which was defined as a ≥25% reduction in maximum standardized uptake values. Common grade 3 and 4 adverse events were asthenia (50.0%) and neutropenia (25.0%)., Conclusions: Dovitinib shows modest antitumor activity in the treatment of ACC., (© 2015 American Cancer Society.)

Purpose: Although ROS1-rearranged non-small cell lung cancer (NSCLC) is sensitive to crizotinib, development of resistance is inevitable. Here, we identified molecular alterations in crizotinib-resistant tumors from two NSCLC patients with the CD74-ROS1 rearrangement, and in HCC78 cells harboring SLC34A2-ROS1 that showed resistance to crizotinib (HCC78CR cells)., Experimental Design: ROS1 kinase domain mutations were examined in fresh tumor tissues from two NSCLC patients and HCC78CR1-3 cells by direct sequencing. Ba/F3 cells expressing ROS1 secondary mutations were constructed to evaluate resistance to crizotinib. An upregulated pathway was identified using phospho-receptor tyrosine kinase array, EGFR signaling antibody array, and RNA sequencing (RNA-seq). Cell proliferation and ROS1 downstream signaling pathways were compared between HCC78 and HCC78CR1-3 cells., Results: The ROS1 G2032R mutation was identified in crizotinib-resistant tumors from one patient. Furthermore, HCC78CR1 and CR2 cells harbored a novel ROS1 L2155S mutation (73.3% and 76.2%, respectively). ROS1 G2032R and L2155S mutations conferred resistance to crizotinib in Ba/F3 cells. Evidence of epithelial-to-mesenchymal transition with downregulated E-cadherin and upregulated vimentin was observed in HCC78CR1-2 cells and in the other patient. RNA-seq and EGFR signaling antibody array revealed that the EGFR pathway was significantly upregulated in HCC78CR3 versus HCC78 cells. Cells with the ROS1 mutation and upregulated EGFR were sensitive to foretinib, an inhibitor of c-MET, VEGFR2, and ROS1 and irreversible EGFR tyrosine kinase inhibitors plus crizotinib, respectively., Conclusions: Molecular changes associated with acquired crizotinib resistance in ROS1-rearranged NSCLC are heterogeneous, including ROS1 tyrosine kinase mutations, EGFR activation, and epithelial-to-mesenchymal transition., (©2015 American Association for Cancer Research.)

Background: Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation are considered mutually exclusive in nonsmall-cell lung cancer (NSCLC). However, sporadic cases having concomitant EGFR and ALK alterations have been reported. The present study aimed to assess the prevalence of NSCLCs with concomitant EGFR and ALK alterations using mutation detection methods with different sensitivity and to propose an effective diagnostic and therapeutic strategy., Patients and Methods: A total of 1458 cases of lung cancer were screened for EGFR and ALK alterations by direct sequencing and flourescence in situ hybridization (FISH), respectively. For the 91 patients identified as having an ALK translocation, peptide nucleic acid (PNA)-clamping real-time PCR, targeted next-generation sequencing (NGS), and mutant-enriched NGS assays were carried out to detect EGFR mutation., Results: EGFR mutations and ALK translocations were observed in 42.4% (612/1445) and 6.3% (91/1445) of NSCLCs by direct sequencing and FISH, respectively. Concomitant EGFR and ALK alterations were detected in four cases, which accounted for 4.4% (4/91) of ALK-translocated NSCLCs. Additional analyses for EGFR using PNA real-time PCR and ultra-deep sequencing by NGS, mutant-enriched NGS increased the detection rate of concomitant EGFR and ALK alterations to 8.8% (8/91), 12.1% (11/91), and 15.4% (14/91) of ALK-translocated NSCLCs, respectively. Of the 14 patients, 3 who were treated with gefitinib showed poor response to gefitinib with stable disease in one and progressive disease in two patients. However, eight patients who received ALK inhibitor (crizotinib or ceritinib) showed good response, with response rate of 87.5% (7/8 with partial response) and durable progression-free survival., Conclusions: A portion of NSCLC patients have concomitant EGFR and ALK alterations and the frequency of co-alteration detection increases when sensitive detection methods for EGFR mutation are applied. ALK inhibitors appear to be effective for patients with co-alterations., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background/aim: The purpose of the present study was to explore the antiproliferative effect of BYL719, a specific inhibitor for phosphatidylinositol 3-kinase (PI3K) p110α, in human head and neck cancer cell lines, as a single agent or in combination with the irreversible EGFR tyrosine kinase inhibitor, dacomitinib., Materials and Methods: Six head and neck cancer cell lines consisting of two PIK3CA mutant cell lines, SNU-1076 and Detroit562, and four PIK3CA wild-type cell lines, SNU-1066, SNU-1041, FaDu and SCC25, were analyzed., Results: The PIK3CA-mutant cell lines were more sensitive to BYL719 than the PIK3CA wild-type cell lines. Following BYL719 treatment, all PIK3CA wild-type cell lines, except for the SNU-1066 cell line, exhibited higher IC50 values compared to the PIK3CA mutant cell lines. Administration of BYL719 induced cell cycle G0/G1 arrest and resulted in increased apoptosis in a dose-dependant manner. Furthermore, the administration of BYL719 reduced the level of p-mTOR, p-AKT and p-S6 expression indicating the down-regulation of downstream signaling., Conclusion: BYL719, a PI3K alpha selective blocker, could be a promising factor in the treatment of head and neck cancer either as a single agent or in combination with dacomitinib., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: Gefitinib is safe for the treatment of non-small cell lung cancer (NSCLC), but some patients experience toxicities and require dose reduction. The purpose of this study was to evaluate the effect of gefitinib dose reduction on survival., Methods: We retrospectively analyzed 263 patients with NSCLC harboring sensitive epidermal growth factor receptor (EGFR) mutation. All patients had recurred or metastatic disease and received gefitinib 250 mg daily as palliative chemotherapy., Results: Of the 263 patients, 23 had gefitinib dose reduction due to toxicities (1 due to mucositis, 5 due to skin rash, 11 due to hepatotoxicity and 6 for both skin and hepatotoxicity). In the dose reduction group, the mean dose intensity was 0.84 (range 0.48-0.98). Patients with dose reduction showed significantly prolonged progression-free survival (PFS) and overall survival (OS) compared to those receiving the standard dose (median PFS: 14.0 vs. 10.6 months, P = 0.042, median OS: 54.5 vs. 29.6, P = 0.020). In multivariate analysis, the effect of dose reduction was not significantly associated with prolonged PFS [hazard ratio (HR) 0.619, 95 % confidence interval (CI) 0.357-1.073, P = 0.085], or OS (HR 0.625, 95 % CI 0.287-1.362, P = 0.237). However, patients receiving low-dose gefitinib tended to have superior survival outcomes compared to those receiving standard-dose gefitinib., Conclusions: The patients experiencing gefitinib dose reduction or short-term treatment interruption due to toxicities did not show inferior survival, compared to those receiving full dose of gefitinib in NSCLC patients with EGFR mutation.

Importance: Current guidelines recommend both epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic chemotherapy drugs as standard treatment options for patients with wild-type (WT) EGFR who were previously treated for non-small cell lung cancer (NSCLC). However, it is not clear that EGFR TKIs are as efficacious as chemotherapy in patients with WT EGFR., Objective: To determine the association between first-generation EGFR TKI vs chemotherapy and survival in advanced NSCLC patients with WT EGFR., Data Sources: PubMed, EMBASE, Cochrane database, and meeting abstracts of the American Society of Clinical Oncology and European Society of Medical Oncology through December 2013., Study Selection: Eligible studies were randomized controlled trials comparing EGFR TKI with conventional chemotherapy in patients with advanced NSCLC. Out of 1947 retrieved articles, 11 trials incorporating 1605 patients with WT EGFR were included., Data Extraction and Synthesis: Two reviewers extracted trial characteristics and outcomes. The risk of bias was evaluated using the Cochrane tool. All measures were pooled using random-effects models and 95% CIs were calculated., Main Outcomes and Measures: The primary outcome was progression-free survival (PFS), measured as hazard ratios (HRs). The secondary outcomes were objective response rate and overall survival, expressed as relative risks and HRs, respectively., Results: Among patients with WT EGFR tumors, chemotherapy was associated with improvement of PFS, compared with TKI (HR for TKI, 1.41; 95% CI, 1.10-1.81). No statistically significant subgroup difference was identified in terms of line of treatment (first-line vs second- or later-line), experimental drug, dominant ethnicity, or EGFR mutation analysis method. Trials using more sensitive platforms than direct sequencing were associated with a significant PFS benefit with chemotherapy (HR for TKI, 1.84; 95% CI, 1.35-2.52). The association of chemotherapy with improvement in PFS was also significant in second- or later-line trials (HR, 1.34; 95% CI, 1.09-1.65). The objective response rate was higher with chemotherapy (92/549, 16.8%, vs 39/540, 7.2%, for TKI; relative risk for TKI, 1.11; 95% CI, 1.02-1.21); however, no statistically significant difference was observed with respect to overall survival (HR for TKI, 1.08; 95% CI, 0.96-1.22)., Conclusions and Relevance: Among patients with advanced NSCLC harboring WT EGFR, conventional chemotherapy, compared with first-generation EGFR TKI, was associated with improvement in PFS but not overall survival.