PURPOSE Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non–small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients. PATIENTS AND METHODS Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status. RESULTS Approximately one quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without ALK mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]). Progression-free survival was similar in patients with and without ALK mutations on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio, 0.81) but significantly longer in patients with ALK mutations identified by tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47). CONCLUSION In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.

MET exon 14 alterations are oncogenic drivers of non-small cell lung cancers (NSCLCs). 1These alterations are associated with increased MET activity and preclinical sensitivity to MET Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms

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The results of recent studies suggest that the mouse Sac (saccharin preference) locus is identical to the Tas1r3 (taste receptor) gene. The goal of this study was to identify Tas1r3 sequence variants associated with saccharin preference in a large number of inbred mouse strains. Initially, we sequenced ϳ6.7 kb of the Tas1r3 gene and its flanking regions from six inbred mouse strains with high and low saccharin preference, including the strains in which the Sac alleles were described originally (C57BL/6J, Sac b ; DBA/2J, Sac d ). Of the 89 sequence variants detected among these six strains, eight polymorphic sites were significantly associated with preferences for 1.6 mM saccharin. Next, each of these eight variant sites were genotyped in 24 additional mouse strains. Analysis of the genotype-phenotype associations in all 30 strains showed the strongest association with saccharin preference at three sites: nucleotide (nt) Ϫ791 (3 bp insertion/deletion), nt ϩ135 (Ser45Ser), and nt ϩ179 (Ile60Thr). We measured Tas1r3 gene expression, transcript size, and T1R3 immunoreactivity in the taste tissue of two inbred mouse strains with different Tas1r3 haplotypes and saccharin preferences. The results of these experiments suggest that the polymorphisms associated with saccharin preference do not act by blocking gene expression, changing alternative splicing, or interfering with protein translation in taste tissue. The amino acid substitution (Ile60Thr) may influence the ability of the protein to form dimers or bind sweeteners. Here, we present data for future studies directed to experimentally confirm the function of these polymorphisms and highlight some of the difficulties of identifying specific DNA sequence variants that underlie quantitative trait loci.

Purpose: To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with advanced tumors.Experimental Design: A 3þ3 design was used in this openlabel, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The starting dose was 80 mg.Results: A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTD was estimated to be 320 mg once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (!6 months).Conclusions: The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors.

Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated. Baseline characteristics were similar in patients with ( = 191) and without ( = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8 T-cell density ≥ versus < median [median (95% CI), not reached (6.83-not reached) versus 3.47 years (1.73-not reached); hazard ratio (HR) 0.40 (95% CI, 0.20-0.81); = 0.009] treated with sunitinib ( = 101), but not with placebo ( = 90). The sensitivity and specificity for CD8 T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1 versus PD-L1 tumors (HR 1.75; = 0.103). Among all patients with PD-L1 tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; = 0.175). Greater CD8 T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. .

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This multicenter, open-label phase II study was conducted to evaluate sunitinib monotherapy in patients with either metastatic or locoregionally recurrent advanced breast cancer. Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. The primary endpoint was objective response rate (ORR); the predefined target ORR was 25 %. All 83 patients enrolled into the study received study treatment. The majority of patients (90 %) had metastatic disease; 92 % had received prior systemic therapies, and 60 % had received two or more regimens for early and/or advanced disease. The ORR was 8 % (95 % exact CI, 4-17), comprising seven partial responses. In patients with superficial lesions (defined as cutaneous or palpable chest wall lesions), the ORR was 20 % (three of 15 evaluable patients), which was higher than that in patients with non-superficial disease (9 %; six of 64 patients). Median progression-free survival in the overall population was 3.6 months (95 % CI, 2.4-3.9); median overall survival was 15.6 months (95 % CI, 14.0-22.7). No new or unexpected safety findings were reported. The most commonly reported adverse events (AEs) were fatigue (60 %), diarrhea (54 %), and nausea (49 %). The most commonly reported grade 3/4 AEs were fatigue (17 %), neutropenia (16 %), and thrombocytopenia (11 %). Four patients (5 %) had a dose reduction due to an AE, and 39 patients (47 %) had temporary discontinuations of therapy due to AEs. Two on-study deaths were reported, one due to a pulmonary embolism (considered related to treatment) and one attributed to dyspnea and a myocardial infarction (considered unrelated to treatment). Patient-reported outcomes suggested that sunitinib treatment did not have a negative impact overall on patients' functional domains or the majority of symptom scales. The trial did not meet its prespecified primary endpoint, and in view of the negative results obtained in several other trials, sunitinib will not be developed further for this indication.