Chintan Shah

Efficacy and safety of carfilzomib in relapsed and/or refractory multiple myeloma: systematic review and meta-analysis of 14 trials

Objective Carfilzomib (Carf) is a second-generation proteasome inhibitor approved for patients with relapsed and/or refractory multiple myeloma (RRMM) who failed ≥ 1 prior lines of therapy. We performed a systematic review of Carf literature with meta-analysis to determine the efficacy and safety in RRMM patients. Methods Based on literature search, we included a total of 14 eligible phase I/II, phase II and phase III Carf based clinical trials. The cumulative incidence and odds ratios (OR) were calculated with random effect model, using ‘’R’’ software with metaphor package. Results 2906 evaluable RRMM patients from published clinical trials included. The pooled overall response rate (ORR) was 45% (95% CI: 29–62). The pooled clinical benefit rate (CBR) was 56% (95% CI: 41–71). OR from 3 randomized clinical trials showed that Carf significantly improved ORR and CBR compared to control groups (OR 2.4, P < 0.0001; 2.02, P = 0.0007, respectively). Subgroup analysis showed significantly better ORR (P < 0.0001) and CBR (P < 0.001) with combination regimens compared to monotherapy. Response was significantly higher with high dose of Carf (>20/27 mg/m2) compared to standard dose (ORR 65% vs. 35%, P = 0.03). Compared to control group, the OR of developing cardiotoxicity (P = 0.002) and hypertension (P < 0.0001) were significantly higher with Carf, while no difference in peripheral neuropathy (P = 0.28). Conclusions Carf produces significantly better responses with acceptable safety profile in RRMM patients. Combination regimens and higher dose Carf offers better response with no significant extra toxicity. Its efficacy is regardless of cytogenetics or disease stage. Incidences of cardiotoxicity and hypertension seem higher with Carf.

Cardiotoxicity associated with carfilzomib: systematic review and meta-analysis

Abstract Carfilzomib is a second-generation proteasome inhibitor (PI) that is approved for patients with relapsed or refractory multiple myeloma (RRMM) who failed ≥1 prior lines of therapy. We performed a systematic review of carfilzomib literature with meta-analysis to determine cumulative incidence of cardiotoxicity. After the literature search, we included a total of 29 eligible phase I/II, phase II and phase III clinical trials which used carfilzomib. The cumulative incidence and overall odds ratios (OR) were calculated with random effect model, using ‘R’ software with metaphor package. A total of 4164 patients with various malignancies were included. The overall estimated cumulative incidence of cardiotoxicity was 8.68% and 4.92%, respectively, for all-grade and high-grade (≥ grade 3) toxicity, which seems higher than other PIs. Compared to control group, the odds of developing cardiotoxicity due to carfilzomib was significantly higher with OR of 2.03 (95% CI: 1.19–3.46, p = .010) and 2.04 (95% CI: 1.31–3.17, p = .002) for all-grades and high grades, respectively. Concomitant immunomodulatory agents seem to increase the risk of cardiotoxicity (high-grade cardiotoxicity 6.45% and 4.34% with and without concomitant immunomodulatory agents, respectively (p = .033)). There was no variation in the incidence of cardiotoxicity among newly diagnosed versus RRMM (p = .38), and high versus standard dose carfilzomib (p = .86).

Survival differences among patients with hepatocellular carcinoma based on the stage of disease and therapy received: pre and post sorafenib era

Background The incidence of hepatocellular carcinoma (HCC) is increasing. Development of newer therapeutic modalities has changed the paradigm of HCC treatment in recent years. So, the aim of our study is to analyze the impact of these treatment modalities into the survival of HCC patients, based on the stage of HCC in real life practice. Methods We analyzed the data from the SEER database: Incidence - SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases, Nov 2015 Sub (1973-2013 varying). Relative survival rates (RSRs) and hazard ratios (HRs) were measured for patients diagnosed with HCC between 2001 and 2013. Rates were compared between pre sorafenib [2001-2007] and post sorafenib [2008-2013] eras. Results A total of 50,088 patients (21,435 in pre sorafenib era and 28,653 in the post-sorafenib era) were included with HCC from SEER database. The median relative survival for the entire population was 14 months with 5-year RSR of 21.20%; 11 months for those diagnosed in 2001-2007 with 5-year RSR 19.30% and 17 months for those diagnosed in 2008-2013 with 5-year RSR 22.40% (P<0.01). This survival improvement was largely limited to HCC patients with single nodule (5-year RSR; 35.1% vs. 37.00% for pre and post sorafenib era respectively; P value <0.01) and multiple nodules without vascular invasion (5-year RSR; 19.90% vs. 22.60% for pre and post sorafenib era respectively; P value <0.01). RSR remained extremely poor with no significant improvement for advanced stage HCC who had vascular invasion (P=0.37) or distant metastasis (P=0.10), respectively for pre and post sorafenib era in each category. Survival improved since 2008, for HCC patients who received either no surgical intervention (P<0.01) or received tumor-directed therapy (P<0.01), however, it remained significantly poor compared to the patients who received lobectomy or hepatectomy and transplant. Approximately 70% of patients from our study population did not receive any HCC directed surgical intervention and among this, more than 40% of patients were with single nodule in the liver. Conclusions Survival in patients with HCC has improved since 2008, which is limited to early stage HCC. Survival of advanced stage HCC patients is extremely poor and has not shown any significant improvement since the approval of sorafenib, emphasizing the need for better therapeutic options. Not receiving any surgical intervention is associated with significantly poor prognosis. Large numbers of early stage HCC patients were not able to receive surgical interventions. This can impose a significant financial burden, as these patients would progress on to the advanced stage, where treatment options are very limited and not as cost-effective. This emphasizes the need for further research to identify various barriers and the possible need for healthcare policy changes.

Abstract 987: Unanticipated cardiotoxicity due to targeted anti-cancer therapy in hematologic malignancies patients: Natural history and risk factors

INTRODUCTION: Unanticipated cardiotoxicity is now identified as a significant clinical problem associated with new anti-cancer targeted agents. Risk factors and natural history are still poorly understood. We aim to determine potential clinical risk factors for cardiotoxicity among patients with hematologic malignancies (HM) who were treated with targeted therapies over a 10-year period. METHODS: We used 114 diagnosis codes for HM and 17 codes for cardiac diseases in order to identify patients in our electronic medical records (EPIC) and identify patients with HM who met above criteria. Cardiotoxicity was defined mainly by left ventricular ejection fraction (LVEF) of RESULTS: Of 820 patients with both HM and cardiac diagnosis, 29 patients developed cardiotoxicity after initiation of targeted therapies. We selected 70 matched controls based on type of targeted therapy. In the study group, the median time from exposure to cardiac event was 120 days (range, 1-1176). Significantly higher number of patients had prior exposure to anthracyclines in study versus control group (65.5% vs 42.8%, P=0.04), however, this was not significant in multivariable analysis. Multiple other variables, including traditional risk factors for heart disease, were analyzed and did not differ significantly between the two groups. Only two variables remained significant in the multivariable analysis, including prior history of DVT/PE (OR 4.88, 95% CI: 1.44-16.54, P=0.011), and Karnofsky score of ≥80% (OR 3.99, 95% CI: 1.51-10.6, P= 0.005). With median follow-up of 27 months (range, 1-120), 17 patients in the study group died, but only 2 of cardiac causes. Repeat echocardiograms showed worsening of LVEF in 4 patients while stable/improved in 23 patients, and 21 patients were able to receive further chemotherapy. There was a trend towards worse overall survival in the study group (P= 0.071). CONCLUSIONS: About 3.5% of patients with HM experience unanticipated cardiotoxicity due to targeted anti-cancer agents with related mortality of 6.8 %. Most patients do well with stable compensated cardiac function and 35% have an objective improvement in LVEF. Risk of cardiotoxicity was significantly higher in patients with known history of DVT/PE. Future studies of possible underlying genetic predisposition will be of great importance. Citation Format: Chintan Shah, Yan Gong, Anita Szady, Qian Sun, carl J. Pepine, Taimour Langaee, Alexandra R. Lucas, Jan S. Moreb. Unanticipated cardiotoxicity due to targeted anti-cancer therapy in hematologic malignancies patients: Natural history and risk factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 987. doi:10.1158/1538-7445.AM2017-987

OAMs at the end: The end of the beginning or the beginning of the end?

229 Background: In 2001, after three months of review, the FDA approved the oral anticancer agent imatinib, making it the fastest approval in FDA history. Since then, the FDA has approved over 40 oral anti-cancer medications (OAMs) and the number continues to rise, transforming cancer care, improving survival in specific cancers and providing new hope. However, the rapid development of OAMs has produced uncertainty over the best use of these new medications, particularly at the end of life. ASCO guidelines recommend against prescribing intravenous chemotherapy within two weeks of expected death, but no such guidelines have yet been developed for OAMs. We describe one institutions experience in prescribing OAMs at the end of life. METHODS An interdisciplinary team of pharmacy, oncology and palliative care specialists undertook an IRB-approved retrospective electronic health record review of patients who died between 1/1/2012 and 12/31/2015 and had been on one of seven oral anti-cancer medications (erlotinib, sunitinib, pazopanib, crizotinib, sorafenib, afatinib, regorafenib). From this cohort, descriptors such as diagnosis, stage, prior lines of therapy, ECOG, BMI and albumin were extracted. RESULTS There were at total of 62 patients who were on at least one of the seven drugs and died during the specified time period. Of these 62 patients, only 2 (3%) had a first prescription for an OAM in the last 30 days of life. Over 90% of the patients that were not prescribed an OAM within 30 days of death were patients with Stage IV disease with a median age of 66 and had an average of 3 prior lines of therapy. Consistent with prognostic models, these patients all had declining albumin, BMI and performance status. CONCLUSIONS Oncologists at this institution rely on prognostic data to gauge when to recommend stopping IV chemotherapy before the last two weeks of life. Extrapolating from ASCO guidelines on the use of IV chemotherapy, these oncologists generally refrain from prescribing OAMs in the last 30 days of life. Unless strong data shows definitive benefit for the use of OAMs, we propose ASCO guidelines recommend not using OAMs during the last two weeks of life.