Capmatinib for patients with non-small cell lung cancer with MET exon 14 skipping mutations: A review of preclinical and clinical studies.

The mesenchymal-epithelial transition (MET) receptor tyrosine kinase binds the hepatocyte growth factor to activate downstream cell signaling pathways involved in cell proliferation, survival, and migration. Several genetic mechanisms can result in an aberrant activation of this receptor in cancer cells. One such activating mechanism involves the acquisition of gene mutations that cause MET exon 14 skipping (METex14) during mRNA splicing. Mutations leading to METex14 are found in approximately 3-4% of patients with non-small cell lung cancer (NSCLC). Accumulating evidence suggests that METex14 is a true, independent oncogenic driver in NSCLC, as well as being an independent prognostic factor for poorer survival in patients with NSCLC. The successes of target therapies have relied on improved understanding of the genetic alterations that lead to the dysregulation of the molecular pathways and more advanced molecular diagnostics. Multiple efforts have been made to target the MET pathway in cancer; however, real clinical progress has only occurred since the emergence of METex14 as a valid biomarker for MET inhibition. Capmatinib is a highly potent and selective type Ib inhibitor of MET. Following preclinical demonstration of activity against MET-dependent cancer cell line growth and MET-driven tumor growth in xenograft models, data from a phase 1 clinical trial showed an acceptable safety profile of capmatinib and preliminary evidence of efficacy in patients with MET-dysregulated NSCLC. The multicohort GEOMETRY mono-1 phase 2 trial reported objective response rates of 68% and 41% in treatment-naïve and in pre-treated patients with METex14 advanced NSCLC, respectively. These results have supported the approval of capmatinib by the US Food and Drug Administration for patients with metastatic NSCLC harboring METex14.

Genomic profiling of cell-free circulating tumor DNA in patients with colorectal cancer and its fidelity to the genomics of the tumor biopsy.

BACKGROUND: Liquid biopsy offers the ability to non-invasively analyze the genome of a tumor through circulating tumor DNA (ctDNA) to identify targetable and prognostic genomic alterations. Few studies have rigorously analyzed ctDNA results and determined the fidelity with which they recapitulate the genomics of a sequenced tissue sample obtained from the same tumor. The clinical utility study (CUS) for the FoundationACT™ ctDNA assay (Foundation Medicine, Cambridge, MA, USA; NCT02620527) is a multi-center prospective clinical study for multiple solid tumor types to compare genomic profiling of paired tissue and blood samples from the same patient. In this subset of the study, paired specimens from 96 patients with colorectal cancer (CRC) were analyzed with comprehensive genomic profiling (CGP) of the tumor tissue sample (FoundationOne®) and blood sample (FoundationACT™). METHODS: Both samples underwent CGP using the hybrid capture-based Illumina Hi-Seq technology. Maximum somatic allele frequency (MSAF) was used to estimate the fraction of ctDNA in the sample. The set of genes and targeted regions common to both tumor and liquid were compared for each subject. RESULTS: Among these patients, 61% were male; 74% had clinical stage IV disease, 19% had clinical stage III disease, and 7% had clinical stage II disease. Time between the tissue biopsy and liquid biopsy (range, 0-709 days) had a significant impact on the positive percent agreement (PPA) between the two assays. Eighty percent of cases had evidence of ctDNA in the blood (MSAF >0). For all cases with MSAF >0, 171 base substitutions and insertions/deletions (indels) were identified in the tumor, and 79% (PPA) of these identical alterations were also identified in matched ctDNA samples; PPA increased to 87% for cases <270 days between the tissue and liquid biopsy, 95% for <90 days, and 100% PPA for <30 days. All known and likely short variants in KRAS, NRAS, and BRAF were analyzed independently as testing of these genes is recommended by the National Comprehensive Cancer Network (NCCN) for patients with CRC and have therapeutic implications. For NCCN genes, PPA was 80% for all time points for short variants; PPA increased to 90% for cases <270 days between the tissue and liquid biopsy. There was high concordance for KRAS G12X between tissue and liquid: overall percent agreement (97%), PPA (93%), negative percent agreement (NPA) (100%), positive predictive value (PPV) (100%), and negative predictive value (NPV) (96%) for the <270 day cohort. CONCLUSIONS: In cases where tumor tissue profiling is not possible, these results provide compelling evidence that genomic profiling of ctDNA in late stage CRC shows a high concordance with tumor tissue sequencing results and can be used to identify most clinically relevant alterations capable of guiding therapy for these patients.

Evaluation of Prophylactic Corticosteroid Eye Drop Use in the Management of Corneal Abnormalities Induced by the Antibody-Drug Conjugate Mirvetuximab Soravtansine.

PURPOSE: Reversible, low-grade ocular adverse events (AE) are associated with administration of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeted antibody-drug conjugate undergoing phase III clinical evaluation in platinum-resistant ovarian cancer. This study investigated the underlying mechanisms of ocular toxicity and evaluated primary prophylactic use of corticosteroid eye drops in patients receiving mirvetuximab soravtansine. PATIENTS AND METHODS: Target expression in the human eye was determined by IHC. The ocular toxicity profile of mirvetuximab soravtansine was assessed preclinically using Dutch-Belted rabbits. In a phase I clinical study, patients with ovarian cancer were treated with 6 mg/kg mirvetuximab soravtansine intravenously once every 3 weeks, including one expansion cohort with corticosteroid eye drops administered daily for the first 10 days of each treatment cycle. RESULTS: FRα expression was absent from human corneal tissues. Ocular abnormalities in the rabbit eye appeared phenotypically consistent with off-target effects on the cornea. Forty patients were enrolled in the expansion cohort. Reversible grade 1 or 2 blurred vision and keratopathy occurred in 16 (40%) and 12 (30%) patients, respectively; no grade 3/4 ocular events were observed. Compared with those patients who did not receive primary prophylaxis, corticosteroid eye drop use resulted in fewer dose reductions (5% vs. 15%) and none discontinued due to ocular AEs. CONCLUSIONS: Preclinical modeling was predictive of the corneal-related symptoms seen in some patients dosed with mirvetuximab soravtansine. Primary prophylactic use of topical corticosteroid eye drops resulted in a trend toward symptomatic improvement and a reduction in ocular AE-related dose modifications in patients treated with mirvetuximab soravtansine.

Adherence to Guidelines for Adjuvant Imatinib Therapy for GIST: A Multi-institutional Analysis.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Adjuvant imatinib therapy improves recurrence-free and overall survival following surgery for patients with high-risk GIST; however, the factors associated with use of adjuvant imatinib therapy are unclear, and adherence to adjuvant imatinib has not been investigated. We sought to determine the clinicopathologic predictors of therapy with adjuvant imatinib following surgical resection for GIST and to determine the utilization of adjuvant imatinib in patients who underwent surgical resection of primary GIST in 2009 or later as recommended by National Comprehensive Cancer network (NCCN) guidelines. METHODS: A multi-institutional cohort including 171 patients who underwent surgery for primary GIST at seven high-volume cancer centers in the USA and Canada between January 2009-December 2012 was used in this study. Receipt of adjuvant imatinib therapy was ascertained, and factors associated with imatinib therapy were analyzed. RESULTS: Following surgery for primary GIST, tumor size (<5.0 cm: ref; 5.0-9.9 cm: odds ratio (OR) 2.36, 95 % confidence interval (CI) 0.74-7.55; >10.0 cm: OR 9.15, 95 % CI 2.28-36.75; p = 0.007), mitotic rate (≤5/50 mitoses per 50 high powered field [HPF]: ref; 6-10/50 HPF: OR 24.91, 95 % CI 3.64-170.35; >10/50 HPF: OR 5.80, 95 % CI 3.64-170.35; p < 0.001), and neoadjuvant therapy (OR 9.52; 95 % CI 2.51-36.14; p = 0.001) were associated with receipt of adjuvant imatinib therapy. Overall, 75 % of patients received appropriate treatment, 23 % of patients were undertreated, and 2 % of patients were overtreated as compared to NCCN guidelines. Adjuvant imatinib therapy was administered in only 53 % of patients for which the NCCN guidelines recommended adjuvant therapy. CONCLUSION: The clinicopathologic factors associated with use of adjuvant imatinib therapy in patients following resection of primary GIST are consistent with established risk factors for recurrence. Adjuvant imatinib therapy remains underutilized in patients with intermediate and high-risk GIST and in patients who receive neoadjuvant therapy. Barriers to adjuvant imatinib therapy in this group of patients needs to be further explored.

Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma (PDA) represent a high-risk group of patients due to tumor or patient-related characteristics. The optimal management of these patients has not been fully defined. MATERIALS AND METHODS: All patients undergoing evaluation for PDA between 2005 and 2008 were identified. Clinical, radiographic, and pathological data were retrospectively reviewed. Patients were staged as borderline resectable using the M.D. Anderson Cancer Center (MDACC) classification. RESULTS: A total of 170 patients with PDA were identified, 40 with borderline resectable disease. Of these, 34 borderline resectable patients (85%) completed neoadjuvant therapy and were restaged; pancreatic resection was completed in 16 patients (46%). Also, 8 patients completed 50 Gy of radiation in 28 fractions in 6 weeks, whereas 8 patients received 50 Gy in 20 fractions in 4 weeks plus chronomodulated capecitabine. An R0 resection was achieved in 12 of the 16 patients (75%). Also, 5 patients (63%) treated in 20 fractions had >90% pathologic response versus 1 (13%) treated in 28 fractions (P < .05). Borderline resectable patients completing surgery had similar survival to patients with resectable disease who underwent surgery. Patients receiving accelerated fractionation radiation had improved survival compared with patients treated with standard fractionation protocol. CONCLUSIONS: A neoadjuvant approach to borderline resectable PDA identifies patients who are most likely to benefit from pancreatic resection. Preoperative capecitabine-based chemoradiation is an effective, well-tolerated treatment for these patients. Neoadjuvant therapy for borderline resectable PDA warrants further investigation using treatment schedules that can safely intensify irradiation dose.