Lung Adenocarcinoma with Anaplastic Lymphoma Kinase (ALK) Rearrangement Presenting as Carcinoma of Unknown Primary Site: Recognition and Treatment Implications.

BACKGROUND: Molecular cancer classifier assays are being used with increasing frequency to predict tissue of origin and direct site-specific therapy for patients with carcinoma of unknown primary site (CUP). OBJECTIVE: We postulated some CUP patients predicted to have non-small-cell lung cancer (NSCLC) by molecular cancer classifier assay may have anaplastic lymphoma kinase (ALK) rearranged tumors, and benefit from treatment with ALK inhibitors. METHODS: We retrospectively reviewed CUP patients who had the 92-gene molecular cancer classifier assay (CancerTYPE ID; bioTheranostics, Inc.) performed on tumor biopsies to identify patients predicted to have NSCLC. Beginning in 2011, we have tested these patients for ALK rearrangements and epidermal growth factor receptor (EGFR) activating mutations, based on the proven therapeutic value of these targets in NSCLC. We identified CUP patients with predicted NSCLC who were subsequently found to have ALK rearrangements. RESULTS: NSCLC was predicted by the molecular cancer classifier assay in 37 of 310 CUP patients. Twenty-one of these patients were tested for ALK rearrangements, and four had an EML4-ALK fusion gene detected. The diagnosis of lung cancer was strongly suggested in only one patient prior to molecular testing. One patient received ALK inhibitor treatment and has had prolonged benefit. CONCLUSIONS: We report on patients with lung adenocarcinoma and ALK rearrangements originally diagnosed as CUP who were identified using a molecular cancer classifier assay. Although ALK inhibitors treatment experience is limited, this newly identifiable group of lung cancer patients should be considered for therapy according to guidelines for stage IV ALK-positive NSCLC.

A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.

PURPOSE: This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS: Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS: The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

Sorafenib and everolimus in advanced clear cell renal carcinoma: a phase I/II trial of the SCRI Oncology Research Consortium.

PURPOSE: To evaluate the feasibility and efficacy of sorafenib and everolimus in renal cell carcinoma (RCC). METHODS: Patients with advanced RCC and ≤ 1 previous targeted therapy were treated. RESULTS: Maximum tolerated doses were sorafenib 200 mg PO BID, everolimus 35 mg PO once weekly. Dose-limiting toxicity was hand-foot syndrome. The response rate was 13%; median PFS was 5.45 months (95% CI: 3.8-7.6). Skin toxicity, fatigue, hypertension, proteinuria, and mucositis (usually Grade 2) were common. CONCLUSIONS: Fifty percent doses of sorafenib and everolimus were required when these drugs were combined. No increase in efficacy was suggested; toxicity was modestly increased.

Phase II trial of ixabepilone and carboplatin with or without bevacizumab in patients with previously untreated advanced non-small-cell lung cancer.

BACKGROUND: Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC. METHOD: Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0-1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30 mg/m2 and carboplatin AUC=6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15 mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles. RESULTS: Eighty-two patients (median age, 63 years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5 months (A) and 15.7 months (B), median progression free survivals were A-5.3 months (95% CI 2.8-8.6) and B-6.7 months (95% CI 5.1-8.4), with median overall survivals of 9.3 months (95% CI 6.4-16.6) 13.2 months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B-23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology. CONCLUSIONS: Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum-doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B.

Weekly docetaxel versus docetaxel/gemcitabine in the treatment of elderly or poor performance status patients with advanced nonsmall cell lung cancer: a randomized phase 3 trial of the Minnie Pearl Cancer Research Network.

BACKGROUND: The aim of this study was to compare the efficacy of single-agent weekly docetaxel with the combination of docetaxel and gemcitabine in elderly and/or poor performance status patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Previously untreated patients with stage IIIB/IV NSCLC who were either >65 years old or had an Eastern Cooperative Oncology Group (ECOG) performance status 2 were eligible. Patients were randomized to receive weekly docetaxel (36 mg/m(2)) Days 1, 8, and 15 or docetaxel (30 mg/m(2))/gemcitabine (800 mg/m(2)) Days 1, 8, and 15. Both regimens were repeated on 28-day cycles for 6 cycles or until disease progression. RESULTS: Three hundred fifty patients were randomized, and 345 received treatment. The median age of patients was 74 years; 38% were >75 years old, and 35% had ECOG performance status 2. Intent-to-treat analysis showed median survivals of 5.5 months versus 5.1 months in the groups receiving docetaxel/gemcitabine versus weekly docetaxel, respectively (P = .65). There were no survival differences detected with docetaxel/gemcitabine versus weekly docetaxel in the 223 patients with good performance status (7.2 months vs 8.0 months, respectively) or in the 122 poor performance status patients (3.8 months vs 2.9 months, respectively). Median time-to-progression was longer in patients who received docetaxel/gemcitabine (4.8 months vs 2.9 months; P = .004). Both regimens were generally well tolerated. CONCLUSIONS: Treatment with docetaxel/gemcitabine produced a modest improvement in time-to-progression but had no impact on survival when compared with single-agent weekly docetaxel in this group of patients. Results with both regimens were disappointing, particularly in patients with poor performance status. Improved treatment for these patients will require the introduction of novel, well-tolerated, targeted agents.