Background: Folate receptor alpha (FRα) is a glycosyl phosphatidylinositol (GPI)-anchored cell surface protein that binds and internalizes folate, which is a cofactor required for DNA/RNA synthesis and cell growth and proliferation. There is a marked up-regulation of FRα in many solid tumors; in contrast, FRα has a minimal expression in adult normal tissue. Mirvetuximab soravtansine is an antibody drug conjugate (ADC) consisting of a maytansinoid, N2'-Deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4), conjugated to an anti-FRα antibody, M9346A. Once bound to the FRα and internalized, the anti-mitotic agents are released and inhibit tubulin polymerization and microtubule assembly, leading to cell death. Here we report the expression of FRα+ on residual tumor samples in metastatic TNBC. Methods: 68 patients (Pts) with stage IV TNBC underwent prescreening to determine if residual tumor tissue expressed FRα. Formalin fixed paraffin embedded (FFPE) samples were sent to Ventana Translational Diagnostics CAP/CLIA Laboratory for analysis using an in-house developed assay, Ventana OptiView DAB Detection kit, and the Ventana BenchMark Ultra automated slide stainer. FRα expression was evaluated by board certified pathologists using a scoring scale 1+ (low), 2+ (medium), and 3+ (high). For the purposes of study entry, FRα expression on cell surface was required to be low, defined as >25% of cells having 1+ expression. Results: 12% (8/68) of evaluated TNBCs had moderate to high rates of FRα expression. The median age of pts screened for FRα was 53 years. Moderate to high FRα expression rates were more common in Black and Asian patients (). Conclusion: Our prospective study has demonstrated that moderate to high expression of FRα in metastatic TNBC is 12%, which is lower than previously reported. An ongoing phase II study will determine efficacy for mirvetuximab soravtansine in advanced TNBC. Acknowledgement: This study was approved and funded in part by the NCCN Oncology Research Program from general research support provided by ImmunoGen, Inc.
Thorunn Helgason, Senthil Damodaran, Kenneth R. Hess, W. Fraser Symmans, and Stacy L. Moulder
Apostolia M. Tsimberidou, Alexandra M. Adamopoulos, Yang Ye, Sarina Piha-Paul, Filip Janku, Siqing Fu, David Hong, Gerald S. Falchook, Aung Naing, Jennifer Wheler, Adoneca Fortier, Razelle Kurzrock, and Kenneth R. Hess
Bendamustine, a cytotoxic alkylating agent, has shown promising results in solid tumors. An investigator-initiated phase I clinical trial of the anti-vascular endothelial growth factor agent bevacizumab and bendamustine was conducted in patients with advanced cancer, because the 2 drugs have different mechanisms of antitumor activity and nonoverlapping toxicity. Patients were treated with escalating doses of intravenous bendamustine (70, 80, 90, and 100 mg/m2; days 1 and 2) and intravenous bevacizumab (10 mg/kg; days 1 and 15). A conventional “3 + 3” study design was used. Forty-two patients were treated: 23 women and 19 men. The median age was 60 years. Patients had received a median of 4 prior therapies (range, 1-10). The most common cancer types were colorectal (n=9), head and neck (n= 8), non-small cell lung (n=6), and breast (n=5). Overall, 117 cycles were administered (median per patient, 2; range, 1-8). No dose-limiting toxicities were noted during the escalation phase. Therefore, the highest dose (level 4) of bendamustine (100 mg/m2) was used in the expansion phase. The most common toxicities were fatigue (n=22), nausea (n=14), anorexia (n=9), and thrombocytopenia (n=7). Of 38 patients who were evaluable for response, 23 (61%) had stable disease, including 2 (5.2%) who had stable disease for 6 months or more (1 with adenoid cystic carcinoma and 1 with non-small cell lung cancer). This regimen of bendamustine (100 mg/m2) and bevacizumab (10 mg/kg) was well tolerated and yielded disease stabilization in selected heavily pretreated patients with advanced cancer.
Sriram Yennurajalingam, Vicente Valero, Zhanni Lu, Diane D. Liu, Naifa L. Busaidy, James M. Reuben, Carolina Diaz Fleming, Janet L. Williams, Kenneth R. Hess, Karen Basen-Engquist, and Eduardo Bruera
Background: Despite the high frequency of cancer-related fatigue (CRF) and its debilitating effects on the quality of life of patients with advanced cancer, there are limited treatment options available. Treatments including physical activity (PA) or dexamethasone (Dex) improve CRF; however, they have lower adherence rates (PA) or long-term adverse effects (Dex). The aim of this study was to determine the feasibility of and preliminary results for the combination of PA and Dex in improving CRF. Methods: In this phase II randomized controlled trial, patients with advanced cancer and CRF scores of ≥4/10 on the Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks with either 4 mg of Dex (LoDex arm) or 8 mg of Dex (HiDex arm) twice a day for 7 days. Feasibility and change in the Functional Assessment of Cancer Illness Therapy-Fatigue subscale (FACIT-F) from baseline to day 8 and day 29 (primary outcome) were assessed. Secondary outcomes included changes in fatigue dimensions (FACIT-General, Patient-Reported Outcomes Measurement Information System [PROMIS]-Fatigue). Results: A total of 60 of 67 (90%) patients were evaluable. All patients were adherent to study medication. We found that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The FACIT-F effect size in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and the effect size in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. We found significant improvements in the Functional Assessment of Cancer Therapy-Physical (P≤.013) and the PROMIS-Fatigue (P≤.003) at days 8 and 29 in both arms. Mixed-model analysis showed a significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F scores were not significantly different between patients in the 2 arms (P=.86). Conclusions: Our study found that the combination therapy of PA with Dex was feasible and resulted in the improvement of CRF. The improvement was seen for up to 3 weeks after the discontinuation of Dex. Further larger studies are justified.
ClinicalTrials.gov identifier: NCT02491632.
Sriram Yennurajalingam, Nizar M. Tannir, Janet L. Williams, Zhanni Lu, Kenneth R. Hess, Susan Frisbee-Hume, Helen L. House, Zita Dubauskas Lim, Kyu-Hyoung Lim, Gabriel Lopez, Akhila Reddy, Ahsan Azhar, Angelique Wong, Sunil M. Patel, Deborah A. Kuban, Ahmed Omar Kaseb, Lorenzo Cohen, and Eduardo Bruera
Background: Despite the high frequency, severity, and effects of cancer-related fatigue (CRF) on the quality of life (QoL) of patients with cancer, limited treatment options are available. The primary objective of this study was to compare the effects of oral Panax ginseng extract (PG) and placebo on CRF. Secondary objectives were to determine the effects of PG on QoL, mood, and function. Methods: In this randomized, double-blind, placebo-controlled study, patients with CRF ≥4/10 on the Edmonton Symptom Assessment System (ESAS) were eligible. Based on a pilot study, we randomized patients to receive either 400 mg of standardized PG twice daily or a matching placebo for 28 days. The primary end point was change in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) subscale from baseline to day 29. Results: Of 127 patients, 112 (88.2%) were evaluable. The mean (SD) FACIT-F subscale scores at baseline, day 15, and day 29 were 22.4 (10.1), 29.9 (10.6), and 30.1 (11.6) for PG (P<.001), and 24.0 (9.4), 30.0 (10.1), and 30.4 (11.5) for placebo (P<.001). Mean (SD) improvement in the FACIT-F subscale at day 29 was not significantly different in the PG than in the placebo group (7.5 [12.7] vs 6.5 [9.9]; P=.67). QoL, anxiety, depression, symptoms, and functional scores were not significantly different between the PG and placebo groups. Improvement in the FACIT-F subscale correlated with baseline scores (P=.0005), Hospital Anxiety and Depression Scale results (P=.032), and sex (P=.023). There were fewer any-grade toxicities in the PG versus placebo group (28/63 vs 33/64; P=.024). Conclusions: Both PG and placebo result in significant improvement in CRF. PG was not significantly superior to placebo after 4 weeks of treatment. There is no justification to recommend the use of PG for CRF. Further studies are needed. Trial Registration: ClinicalTrials.gov identifier: NCT01375114.