Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial.

BACKGROUND: Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. METHODS: We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting. FINDINGS: Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4-20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3-7·8] vs 4·5 months [3·0-5·7]; hazard ratio 0·66 [0·51-0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]). INTERPRETATION: Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs. FUNDING: Amgen.

Durvalumab real-world treatment patterns and outcomes in patients with stage III non-small-cell lung cancer treated in a US community setting.

Background: For eligible patients with unresectable stage III non-small-cell lung cancer, durvalumab consolidation therapy following chemoradiotherapy is the standard of care. Methods: This was a retrospective study of durvalumab-treated patients diagnosed between 1 August 2017 and 29 February 2020. Electronic health record data were assessed descriptively, with Kaplan-Meier methods used for duration of treatment and overall survival (OS). Results: Among 528 patients (median age 70 years, 51.5% male), the median duration of treatment was 7.1 months (95% CI: 6.0-9.0). Estimated 1- and 2-year OS rates were 83.5 and 64.0%, respectively, with median OS not reached. Conclusion: This study confirmed an OS benefit with durvalumab after chemoradiotherapy in a real-world setting, consistent with the results from the PACIFIC phase III clinical trial.

What is this article about? Durvalumab is a treatment approved for patients with a specific type of lung cancer. Clinical trials have shown durvalumab is an effective therapy for these patients. We conducted this study to better understand what happens to patients treated with durvalumab who were not enrolled in clinical trials. What were the results? Patients who were treated with durvalumab in this study tended to survive as long as patients who received it as part of a clinical trial. What do the results of the study mean? Studies like this one may better represent patients who are less likely to take part in clinical trials. Future studies may examine long-term outcomes of durvalumab and factors associated with better outcomes.

Treatment patterns in patients with metastatic non-small-cell lung cancer in the era of immunotherapy.

Background: Chemotherapy (CT) alone was previously standard first-line (1L) therapy for metastatic non-small-cell lung cancer (NSCLC) but alternative treatments, including immunotherapy (I-O), are now available. Patients & methods: In this retrospective study, adults with stage IV NSCLC who initiated 1L treatment between 1 August 2018 and 31 December 2019 and had ≥2 visits were identified in the Flatiron database. Patients were followed up until 30 June 2020. Baseline characteristics and treatment patterns were described by treatment group: CT, I-O + CT, I-O monotherapy and other. Results: Approximately 20% of patients received 1L CT in the 2018-2019 timeframe studied; these patients tended to have squamous histology and low (≤49%) programmed death ligand-1 expression. Conclusion: A proportion of patients with metastatic NSCLC still receive 1L CT despite the availability and widespread use of I-O therapies.

Treatment patterns and outcomes of patients with advanced malignant pleural mesothelioma in a community practice setting.

Aim: To assess real-world treatment patterns and outcomes among patients with advanced malignant pleural mesothelioma. Patients & methods: Retrospective database analysis. Results: In all, 469 patients received first-line systemic anticancer therapy (SACT) at community centers. Median follow-up from diagnosis was 11.6 months. Pemetrexed + platinum was the most common first-line SACT; similar proportions of patients received cisplatin or carboplatin with pemetrexed. Only a small proportion of patients received second- and third-line therapies. Median overall survival for first-line SACT was 12.0 months (95% CI: 10.7-14.2). Results were similar with pemetrexed + cisplatin and pemetrexed + carboplatin. Median overall survival with second-line SACT was 6.4 months (95% CI: 5.1-7.6). Conclusion: There is a need for more effective SACTs for advanced malignant pleural mesothelioma.

Lay abstract Real-world data on treatment patterns and outcomes among patients with advanced malignant pleural mesothelioma (MPM), largely a cancer of the lining surrounding the lungs, are limited. In this analysis based on patients treated in the USA, pemetrexed + cisplatin or pemetrexed + carboplatin was shown to be the most common treatment received by patients when first diagnosed with advanced MPM. Only a few patients received any subsequent treatments. Survival among patients receiving treatment was poor, with a median of approximately 12 months. Immunotherapy regimens are currently being investigated, with nivolumab + ipilimumab being the first immunotherapy regimen approved in October 2020 for the treatment of advanced MPM.

Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis.

Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles.

Human Direct Skin Feeding Versus Membrane Feeding to Assess the Mosquitocidal Efficacy of High-Dose Ivermectin (IVERMAL Trial).

BACKGROUND: Ivermectin is being considered for mass drug administration for malaria, due to its ability to kill mosquitoes feeding on recently treated individuals. In a recent trial, 3-day courses of 300 and 600 mcg/kg/day were shown to kill Anopheles mosquitoes for at least 28 days post-treatment when fed patients' venous blood using membrane feeding assays. Direct skin feeding on humans may lead to higher mosquito mortality, as ivermectin capillary concentrations are higher. We compared mosquito mortality following direct skin and membrane feeding. METHODS: We conducted a mosquito feeding study, nested within a randomized, double-blind, placebo-controlled trial of 141 adults with uncomplicated malaria in Kenya, comparing 3 days of ivermectin 300 mcg/kg/day, ivermectin 600 mcg/kg/day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. On post-treatment day 7, direct skin and membrane feeding assays were conducted using laboratory-reared Anopheles gambiae sensu stricto. Mosquito survival was assessed daily for 28 days post-feeding. RESULTS: Between July 20, 2015, and May 7, 2016, 69 of 141 patients participated in both direct skin and membrane feeding (placebo, n = 23; 300 mcg/kg/day, n = 24; 600 mcg/kg/day, n = 22). The 14-day post-feeding mortality for mosquitoes fed 7 days post-treatment on blood from pooled patients in both ivermectin arms was similar with direct skin feeding (mosquitoes observed, n = 2941) versus membrane feeding (mosquitoes observed, n = 7380): cumulative mortality (risk ratio 0.99, 95% confidence interval [CI] 0.95-1.03, P = .69) and survival time (hazard ratio 0.96, 95% CI 0.91-1.02, P = .19). Results were consistent by sex, by body mass index, and across the range of ivermectin capillary concentrations studied (0.72-73.9 ng/mL). CONCLUSIONS: Direct skin feeding and membrane feeding on day 7 resulted in similar mosquitocidal effects of ivermectin across a wide range of drug concentrations, suggesting that the mosquitocidal effects seen with membrane feeding accurately reflect those of natural biting. Membrane feeding, which is more patient friendly and ethically acceptable, can likely reliably be used to assess ivermectin's mosquitocidal efficacy. CLINICAL TRIALS REGISTRATION: NCT02511353.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial.

BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

Intra-individual effects of food upon the pharmacokinetics of rifampicin and isoniazid.

Background: Poor response to TB therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic parameters can be affected by comorbidities or the interaction of drugs with food. Objectives: This study aimed to determine the effect of food intake upon pharmacokinetics of rifampicin and isoniazid in a Peruvian population with TB. Methods: Rifampicin and isoniazid levels were analysed at 2, 4 and 6 h after drug intake in both fasting and non-fasting states using LC-MS methods. Results: Sixty patients participated in the study. The median rifampicin Cmax and AUC0-6 were higher during fasting than non-fasting: 7.02 versus 6.59 mg/L (P = 0.054) and 28.64 versus 24.31 mg·h/L (P = 0.002). There was a statistically significant delay overall of non-fasting Tmax compared with the fasting state Tmax (P = 0.005). In the multivariate analysis, besides the effect of fasting, Cmax for females was 20% higher than for males (P = 0.03). Concerning isoniazid, there were significant differences in the Cmax during non-fasting (median = 3.51 mg/L) compared with fasting (4.54 mg/L). The isoniazid dose received had an effect upon the isoniazid levels (1.26, P = 0.038). In the multivariate analysis, isoniazid exposure during fasting was found to be 14% higher than during non-fasting (CI = 1.02-1.28, P < 0.001). Neither radiological extent of the disease nor consumption of food with drug intake nor pharmacokinetics of rifampicin or isoniazid was associated with a poorer treatment outcome. Conclusions: Rifampicin in particular and isoniazid pharmacokinetics were significantly affected by the intake of the drug with food between and within individuals.

Erlotinib plus either pazopanib or placebo in patients with previously treated advanced non-small cell lung cancer: A randomized, placebo-controlled phase 2 trial with correlated serum proteomic signatures.

BACKGROUND: This study compared the efficacy and safety of treatment with erlotinib plus pazopanib versus erlotinib plus placebo in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients with progressive-stage IV NSCLC after either 1 or 2 previous chemotherapy regimens were randomized to receive erlotinib (150 mg by mouth daily) with either pazopanib (600 mg by mouth daily) or placebo. During treatment, patients were evaluated every 8 weeks until disease progression or unacceptable toxicity. After a study amendment, pretreatment serum specimens for the VeriStrat assay were collected. The predictive value of the VeriStrat score (good vs poor) for progression-free survival (PFS) and overall survival (OS) was assessed in the overall population and in each treatment group. RESULTS: One hundred ninety-two eligible patients were randomized between February 2010 and February 2011. PFS was prolonged with erlotinib plus pazopanib versus erlotinib plus placebo (median, 2.6 vs 1.8 months; hazard ratio, 0.58; P = .001). There was no difference in the OS of the 2 groups. A good VeriStrat score predicted longer PFS and OS in the entire group and predicted longer PFS in the subgroup receiving erlotinib plus pazopanib. The addition of pazopanib increased toxicity, and this was consistent with the known toxicity profile. CONCLUSIONS: The addition of pazopanib to erlotinib in an unselected group of patients with previously treated NSCLC improved PFS and increased treatment-related toxicity, but it had no influence on OS. The efficacy of both regimens was modest. Patients receiving erlotinib plus pazopanib had longer PFS if they had a good VeriStrat score versus a poor one. Cancer 2018;124:2355-64. © 2018 American Cancer Society.

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer.

BACKGROUND: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. METHODS: We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. RESULTS: The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group. CONCLUSIONS: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis.

Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0-∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.

A Randomized, Double-Blinded, Phase II Trial of Gemcitabine and Nab-Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial.

LESSONS LEARNED: The addition of the heat shock protein 27 (Hsp27)-targeting antisense oligonucleotide, apatorsen, to a standard first-line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation. BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of gemcitabine/nab-paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer. METHODS: Patients were randomized 1:1 to Arm A (gemcitabine/nab-paclitaxel plus apatorsen) or Arm B (gemcitabine/nab-paclitaxel plus placebo). Treatment was administered in 28-day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS). RESULTS: One hundred thirty-two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment-related adverse events for both arms. Median progression-free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor-prognosis subgroup who may have derived modest benefit from addition of apatorsen. CONCLUSION: Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first-line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.

Phase Ib study of the mitochondrial inhibitor ME-344 plus topotecan in patients with previously treated, locally advanced or metastatic small cell lung, ovarian and cervical cancers.

Background This multicenter, open-label, phase Ib study was designed to assess the safety, pharmacokinetics and preliminary efficacy of ME-344, a mitochondrial inhibitor, administered in combination with the topoisomerase I inhibitor, topotecan, in patients with previously treated, locally advanced or metastatic small cell lung (SCLC), ovarian and cervical cancers. Patients and methods In Part 1, patients received ME-344 10 mg/kg intravenously weekly on days 1, 8, 15 and 22 in combination with topotecan 4 mg/m2 on days 1, 8, and 15 of a 28 day cycle. Cycles were repeated until disease progression or unacceptable toxicity. Patients were evaluated for dose-limiting toxicity (DLT) in cycle 1 and ME-344 pharmacokinetic samples were obtained. In Part 2, patients with locally advanced or metastatic SCLC and ovarian cancer were enrolled in expansion cohorts treated at the recommended phase II dose (RP2D) determined in Part 1. Results Fourteen patients were enrolled in Part 1 and no DLTs were observed. The RP2D of ME-344 in combination with topotecan was established as 10 mg/kg. In Part 2, 32 patients were enrolled. The most common treatment-emergent all-grade and grade 3/4 toxicities included fatigue (65.2%, 6.5%), neutropenia (56.5%, 43.5%) and thrombocytopenia (50%, 23.9%). One patient with recurrent ovarian cancer experienced a partial response by RECIST 1.1 and 21 patients achieved stable disease as best response. Conclusions The combination of ME-344 10 mg/kg weekly and topotecan 4 mg/m2 was tolerable, however, the degree of anti-cancer activity does not support further investigation of the combination in unselected patients with SCLC, ovarian and cervical cancers.

First-Line Carboplatin, Pemetrexed, and Panitumumab in Patients with Advanced Non-Squamous KRAS Wild Type (WT) Non-Small-Cell Lung Cancer (NSCLC).

BACKGROUND: We added panitumumab to standard combination chemotherapy as first-line treatment for patients with advanced KRAS WT non-squamous NSCLC. METHODS: Patients received panitumumab 9 mg/kg IV, pemetrexed 500 mg/m2 IV, and carboplatin AUC = 6 IV every 21 days. After 6 cycles, maintenance therapy with panitumumab and pemetrexed was administered every 21 days until progressive disease or unacceptable toxicity. RESULTS: 29 of 66 patients (44%) had objective responses. The median TTP was 6 months; median overall survival (OS) was 17 months. Panitumumab increased treatment-related toxicity, notably skin rash. CONCLUSIONS: The addition of panitumumab increased toxicity, and had no discernible impact on efficacy.

A Phase II Study of FOLFOXIRI Plus Panitumumab Followed by Evaluation for Resection in Patients With Metastatic KRAS Wild-Type Colorectal Cancer With Liver Metastases Only.

BACKGROUND: Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis. METHODS: Patients received FOLFOXIRI (5-FU, 3,200 mg/m(2), 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m(2) i.v.; irinotecan, 125 mg/m(2); oxaliplatin, 85 mg/m(2) i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate. RESULTS: Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found. CONCLUSION: KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.

A Phase II Study of the Combination of Bevacizumab, Pertuzumab, and Octreotide LAR for Patients with Advanced Neuroendocrine Cancers.

PURPOSE: To evaluate efficacy and safety of bevacizumab, pertuzumab, and octreotide depot for advanced neuroendocrine tumors. METHODS: Patients received bevacizumab 15 mg/kg and pertuzumab 420 mg IV q21 days with octreotide depot 30 mg IM q28 days. RESULTS: Toxicities in 43 patients included diarrhea (63%), fatigue (63%), hypertension (44%), and nausea (44%). Reversible G3 hypertension (26%) and LVEF decline (9%) occurred. 7/43 patients achieved objective response (typical carcinoid, 5; pancreatic NET, 2). Median PFS and OS were 6.5 and 26.4 months, respectively. DISCUSSION: Bevacizumab, pertuzumab, and octreotide depot was well-tolerated with a 16% ORR. Results in the well-differentiated carcinoid tumors are thought provoking.

A phase II study of two dose levels of ofatumumab induction followed by maintenance therapy in symptomatic, previously untreated chronic lymphocytic leukemia.

Despite the recent advances in treatment of CLL with targeted agents such as ibrutinib, availability of nonchemotherapy based therapies is desired. Given the 58% response rate (1996 NCI-WG criteria) of single agent ofatumumab in CLL refractory to fludarabine and alemtuzumab, we initiated a phase II trial examining response, safety, and progression-free survival (PFS) of ofatumumab as front-line monotherapy. Patients enrolled included untreated, symptomatic CLL patients over the age of 65 or those who were inappropriate/did not desire chemotherapy. Two cohorts were enrolled sequentially examining either 1 g (33 patients) or 2 g (44 patients) weekly for 8 weeks followed by maintenance dosing every 2 months for a total of 24 months. Patients receiving 1 g were older than those receiving 2 g, but there were no significant differences in other clinical characteristics. The best overall response rates in the 1 and 2 g patient cohorts were 72 and 89% (1996 NCI-WG criteria), respectively (54 and 68%, respectively, using 2008 IWCLL criteria). All but two responses were partial. The 24-month estimated PFS rates were 46 and 78%, respectively. Response and PFS was lower in del(17p) and del(11q) CLL patients. Differences in PFS between dose cohorts were statistically significant and remained so when adjusting for age or high-risk cytogenetics. Toxicity of this treatment was mild with only six patients not completing therapy due to toxicity. Ofatumumab induction followed by maintenance therapy in untreated CLL represents a well-tolerated and active regimen, particularly with the 2 g of ofatumumab. Am. J. Hematol. 91:1020-1025, 2016. © 2016 Wiley Periodicals, Inc.