Real world risk of infusion reactions and effectiveness of front-line obinutuzumab plus chlorambucil compared with other frontline treatments for chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in North America. Previous studies have shown improved progression free survival (PFS) and response rates in unfit patients treated with obinutuzumab compared to other regimens. The aim of this study was to evaluate the obinutuzumab-chlorambucil regimen in the context of historical treatments and first-dose infusion reactions at CancerCare Manitoba (CCMB). METHODS: A retrospective chart review was conducted for patients treated with obinutuzumab from January 1, 2014 to December 31, 2017 at CCMB. A minimum data set was extracted for patients treated with other front-line therapies. Descriptive statistics were used to evaluate patient demographics, toxicity, duration and dosing of obinutuzumab treatment. Kaplan-Meier curves were used to evaluate time-to-next-treatment (TTNT), overall survival (OS) and PFS for patients treated with obinutuzumab. A multivariable logistic regression model was used to investigate associations between infusion related reactions (IRRs) and age at treatment, pre-treatment lymphocyte count, cumulative illness rating scale (CIRS) and receipt of prior chemotherapy. RESULTS: Forty seven percent of patients receiving frontline therapy received chlorambucil and obinutuzumab. Sixty-seven patients were treated with obinutuzumab and consisted of 36 males (53.7%) and 31 females (46.3%) with 29 patients (43.3%) over age 75 years. Rates of grade 3 and 4 obinutuzumab IRRs were lower (6%) compared to the CLL11 clinical trial (20%) due to local practices including slower infusion rates and using chlorambucil before starting obinutuzumab treatment. Many patients had difficulty tolerating the full dosage of chlorambucil. Only 26 patients (38.8%) had their dose of chlorambucil escalated to the full dose of 0.5 mg/kg. In addition, only 18 patients (26.9%) received all doses of obinutuzumab and all 12 doses of chlorambucil. CONCLUSIONS: In summary, first dose infusion reactions with obinutuzumab can be markedly reduced by using chlorambucil to decrease the lymphocyte count before obinutuzumab and by using a very slow initial obinutuzumab infusion rate. Modifications in chlorambucil dosing and obinutuzumab administration can improve tolerance without significant loss in efficacy.

Ascites predicts treatment benefit of bevacizumab in front-line therapy of advanced epithelial ovarian, fallopian tube and peritoneal cancers: an NRG Oncology/GOG study.

OBJECTIVES: Predictive factors for efficacy of bevacizumab in advanced ovarian cancer have remained elusive. We investigated ascites both as a prognostic factor and as a predictor of efficacy for bevacizumab. METHODS: Using data from GOG 0218, patients receiving cytotoxic therapy plus concurrent and maintenance bevacizumab were compared to those receiving cytotoxic therapy plus placebo. The presence of ascites was determined prospectively. Chi-square and Wilcoxon-Mann-Whitney tests compared baseline variables between subgroups. Survival was estimated by Kaplan-Meier method, and Cox proportional hazard models were used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on survival. RESULTS: Treatment arms were balanced with respect to ascites and other prognostic factors. Overall, 886 (80%) women had ascites, 221 (20%) did not. Those with ascites were more likely to have: poorer performance status (p<0.001); serous histology (p=0.012); higher baseline CA125 (p<0.001); and suboptimal cytoreduction (p=0.004). In multivariate survival analysis, ascites was prognostic of poor OS (Adjusted HR 1.22, 95% CI 1.00-1.48, p=0.045), but not PFS. In predictive analysis, patients without ascites treated with bevacizumab had no significant improvement in either PFS (AHR 0.81, 95% CI 0.59-1.10, p=0.18) or OS (AHR 0.94, 95% CI 0.65-1.36, p=0.76). Patients with ascites treated with bevacizumab had significantly improved PFS (AHR 0.71, 95% CI 0.62-0.81, p<0.001) and OS (AHR 0.82, 95% CI 0.70-0.96, p=0.014). CONCLUSIONS: Ascites in women with advanced ovarian cancer is prognostic of poor overall survival. Ascites may predict the population of women more likely to derive long-term benefit from bevacizumab.

Front-line lenalidomide therapy in patients with newly diagnosed multiple myeloma.

The availability of novel drugs with different and innovative mechanisms of action such as proteasome inhibitors such as bortezomib and immunomdulatory agents as thalidomide and lenalidomide have changed the landscape of the treatment of patients with newly diagnosed multiple myeloma, allowing the development of several new therapeutic regimens both for transplant-eligible and -ineligible patients. Among these new agents, lenalidomide has become one of the most commonly used in these patients. In this article, we review the current state-of-the-art of different induction and maintenance lenalidomide-containing regimens administered in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. We also discuss the safety profile and potential long-term side effects of this drug and analyze its utility in certain subgroups of patients like those with high-risk disease or different degrees of renal impairment.

Bendamustine and rituximab as frontline therapy in extranodal marginal zone lymphoma: a single-institution experience.

Extranodal marginal zone lymphoma (EMZL) encompasses 70% of cases of marginal zone lymphoma. Frontline bendamustine and rituximab (BR) were derived from trials involving other indolent non-Hodgkin's lymphomas. Only one trial has evaluated frontline BR prospectively in EMZL. This retrospective study reports outcomes among EMZL patients receiving frontline BR. Twenty-five patients were included with a median age of 69 years (40-81). Five (20.0%) patients had stage I/II disease, and 20 (80.0%) had stage III/IV disease. The median number of cycles was 6.0 (3.0-6.0). Maintenance rituximab was administered to 10 (41.7%) individuals. Overall response rate (ORR) was 100.0% (60.0% complete response, 40.0% partial response). Medians of overall survival and progression-free survival were not reached. The estimated 2-year progression-free survival was 85.2% and overall survival was 100.0%. Four (16.6%) patients had infections related to treatment; 3 (12.0%) transformed to diffuse large B-cell lymphoma; 5 (20.8%) had a relapse or progression of EMZL; and 3 (12.0%) died unrelated to BR. BR is an efficacious and well-tolerated front-line regimen for EMZL with response data consistent with existing literature.

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study.

BACKGROUND: Cadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. TRIAL DESIGN: This single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. RESULTS: The study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

Front-line treatment for advanced non-small-cell lung cancer and ALK fusion: a network meta-analysis.

Background: It remains unknown what is the optimal front-line choice for advanced non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) fusion. Methods: We conducted a systematic review and network meta-analysis of randomized phase III clinical trials comparing two or more treatments as the front-line setting for patients with advanced ALK-positive NSCLC. Results: Nine phase III randomized clinical trials with 2367 patients were included. As to efficacy, lorlatinib had the most favorable progression-free survival [PFS; surface under the cumulative ranking curve (SUCRA) = 98.4%] in the first-line setting, with noticeable outcome benefits versus chemotherapy [hazard ratio (HR): 0.12; 95% confidence interval (CI): 0.08-0.19], crizotinib (HR: 0.28; 95% CI: 0.19-0.41), ceritinib (HR: 0.22; 95% CI: 0.13-0.37), and brigatinib (HR: 0.58; 95% CI: 0.35-0.96), as well as beneficial trends when compared with alectinib (HR: 0.66; 95% CI: 0.41-1.04) and ensartinib (HR: 0.62; 95% CI: 0.36-1.08). Meanwhile, alectinib showed the optimal overall survival (OS; SUCRA = 91.2%), with significant improvements over chemotherapy (HR: 0.47; 95% CI: 0.30-0.72) and crizotinib (HR: 0.58; 95% CI: 0.41-0.82). Similarly, brigatinib also displayed prolonged OS compared with crizotinib after adjustment for crossover by the marginal structural model (HR: 0.54; 95% CI: 0.31-0.92). In terms of safety, alectinib had the fewest grade 3-5 adverse events (SUCRA = 98.9%), with marked advantages versus crizotinib [odds ratio (OR): 0.67; 95% CI: 0.46-0.97], ceritinib (OR: 0.21; 95% CI: 0.10-0.43), brigatinib (OR: 0.37; 95% CI: 0.20-0.69), ensartinib (OR: 0.48; 95% CI: 0.27-0.89), and lorlatinib (OR: 0.30; 95% CI: 0.16-0.54). Conclusions: Lorlatinib may have advantageous PFS compared with other agents but a greater risk of severe toxicity. Second-generation inhibitors, including alectinib, brigatinib, and ensartinib, provide major efficacy with less toxicity and remain appropriate regimens in the front-line setting.

A phase II randomized study evaluating azacitidine versus conventional care regimens in newly diagnosed elderly Japanese patients with unfavorable acute myeloid leukemia.

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients.

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia.

BACKGROUND: Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML. PATIENTS AND METHODS: Primary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m2 on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle. RESULTS: Twenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3. CONCLUSION: Multiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.

Hopes and failures in front-line ovarian cancer therapy.

Through the last three decades, the combination of paclitaxel and carboplatin remains the standard of care chemotherapy in newly diagnosed epithelial ovarian cancer (EOC). Based on a single trial, first-line maintenance therapy with angiogenesis inhibitor bevacizumab was approved in Europe and widely applied. In 2018, based on a second trial bevacizumab was approved for first-line maintenance in the United States. Despite complete remission upon chemotherapy, the majority of the patients recur. A large number of randomized trials were conducted to explore the optimal front-line therapy regimen, but neither dose-densing, nor adding of a third chemotherapy agent or intraperitoneal administration could improve overall survival (OS). Also implementation of hyperthermic intraperitoneal chemotherapy (HIPEC) or the neoadjuvant approach failed to improve OS. Recently, maintenance therapy with PARP inhibitors showed encouraging results in patients with BRCA1/2 mutation. Further trials with targeted therapies are ongoing. Here we review the achievements of front-line therapy in primary advanced EOC through the last three decades and discuss future treatment strategies.

Comparison of Time to Next Treatment, Health Care Resource Utilization, and Costs in Patients with Chronic Lymphocytic Leukemia Initiated on Front-line Ibrutinib or Chemoimmunotherapy.

BACKGROUND: Studies assessing ibrutinib's economic burden versus chemoimmunotherapy (CIT) focused on pharmacy costs but not medical costs. This study compared time to next treatment (TTNT), health care resource utilization (HRU), and total direct costs among patients with chronic lymphocytic leukemia (CLL) initiating front-line ibrutinib single agent (Ibr) or CIT. MATERIALS AND METHODS: Optum Clinformatics Extended DataMart De-Identified Databases were used to identify adults with ≥ 2 claims with a CLL diagnosis initiating front-line Ibr or CIT from February 12, 2014 to June 30, 2017. Inverse probability of treatment weighting was used to control for potential differences in baseline characteristics between the Ibr and CIT cohorts. Two periods were considered: entire front-line therapy (until initiation of second-line therapy) and first 6 months of front-line therapy. Comparisons with a subgroup of CIT patients initiating bendamustine/rituximab (BR) were also conducted. RESULTS: TTNT was significantly longer for Ibr (N = 322) relative to CIT (N = 839; hazard ratio, 0.54; P = .0163; Kaplan-Meier rates [24 months]: Ibr = 88.6%, CIT = 75.9%) and the subset of CIT patients treated with BR (N = 455; hazard ratio, 0.54; P = .0208; Kaplan-Meier rates [24 months]: Ibr = 89.0%, BR = 79.0%). During the entire front-line therapy, Ibr patients had significantly fewer monthly days with outpatient visits (rate ratio = 0.75; P = .0200). Ibrutinib's higher pharmacy costs (mean monthly cost difference [MMCD] = $6,849; P < .0001) were offset by lower medical costs (MMCD = -$10,615; P < .0001), yielding net savings (MMCD = -$3,766; P < .0001) versus CIT. Ibr was associated with net savings (MMCD = -$5,569; P < .0001) versus BR. Cost savings and reductions in HRU were more pronounced during the first 6 months of front-line therapy. CONCLUSION: During front-line CLL treatment, Ibr was associated with longer TTNT, fewer monthly days with outpatient visits, and net monthly total cost reduction versus CIT and BR.

Which therapies will move to the front line for multiple myeloma?

INTRODUCTION: Despite substantial progress, multiple myeloma (MM) remains an incurable disease. Recently the availability of several novel drugs with different and innovative mechanisms of action (daratumumab, elotuzumab, carfilzomib, ixazomib, and panobinostat) has increased the therapeutic options but has also increased complexity in the management of patients with MM. Areas covered: The outstanding results observed in the relapsed setting with regimens including these new drugs has provided the investigators with several treatment options that are being tested also in patients with newly diagnosed MM. Fully published phase 2 and randomized, phase 3 trials including new drugs in patients with relapsed and/or refractory MM have been reviewed. In addition, the progressive incorporation of these new drugs in the front-line treatment of MM and the potential impact of these new therapies in the management of patients with newly diagnosed MM has also been addressed. Expert commentary: In the near future, several novel anti-MM drugs will move from the relapsed to the front-line setting. While the increasing range of effective therapeutic agents is very encouraging it adds to the complexity of treatment decisions and prospective trials are needed to help clinicians to determine which could be the best therapeutic approaches for the different subgroups of patients with newly diagnosed MM.

Review of thalidomide in the treatment of newly diagnosed multiple myeloma.

The role of thalidomide has been well established in the setting of relapsed or refractory multiple myeloma (MM). More recently, studies have been focused on upfront induction therapy. In newly diagnosed MM patients, thalidomide improved the response rates and the event-free survival induced by both high-dose and conventional chemotherapy regimens. The effect on survival needs to be further investigated. The efficacy of this drug is counterbalanced by a significant rate of both acute and long-term toxicities. Thus best timing of initiation, dosing schemes and duration of therapy is still unclear. Evidence is now emerging that clinical response can be achieved also at lower doses with minimal long term toxicity.