ESR1 Mutations Predict Response to Endocrine Therapy in Advanced Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop breast cancer during their life time. Approximately, 255,180 new cases of breast cancer will be diagnosed in 2017 and 41,070 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy which is the cornerstone of their treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX® (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.

Upon development of metastatic disease, a subgroup of these patients, develop resistance to endocrine therapy. The most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting are the ESR1 mutations. These mutations promote ligand independent estrogen receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315) ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER positive, HER negative advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% vs 11%).

Droplet digital Polymerase Chain Reaction (ddPCR) is a highly sensitive and specific technique and can detect ESR1 mutations in the plasma. Retrospective studies have shown that ESR1 mutations detected in plasma cfDNA (cell free DNA) by ddPCR were associated with a lack of response to subsequent AI therapy. The authors in this publication used baseline plasma samples and assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials, the SoFEA trial and PALOMA-3 trial, which are representative of the current standard of care for ER positive advanced breast cancer.

In the SoFEA trial (Study of Faslodex With or Without Concomitant Arimidex), AROMASIN® (Exemestane), a steroidal AI, was compared with FASLODEX® (Fulvestrant)-containing regimens, in patients with prior sensitivity to nonsteroidal AIs (Letrozole and Anastrozole). In the PALOMA3 trial (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, FASLODEX® plus placebo was compared with FASLODEX® plus IBRANCE® (Palbociclib), in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital Polymerase Chain Reaction. (Multiplex PCR amplifies several different DNA sequences simultaneously and more information can be obtained from a single test run).

In the SoFEA trial, ESR1 mutations were found in 39.1% of patients of whom 49.1% were polyclonal. Polyclonal ESR1 mutations suggest that biopsy from a single metastatic site would fail to show capture these mutations. Patients with ESR1 mutations on FASLODEX® had improved Progression Free Survival (PFS) compared with AROMASIN® (HR=0.52; P=0.02). Patients with wild-type ESR1 had similar PFS after receiving either treatment (HR=1.07; P=0 .77). Ability to detect these mutations was not impacted by delays in processing of archival plasma. In the PALOMA3 trial, ESR1 mutations were found in the plasma of 25.3% of patients of whom 28.6% were polyclonal ESR1 mutations. The combination of FASLODEX® plus IBRANCE® improved PFS compared with FASLODEX® plus placebo in both ESR1 mutant (HR=0.43; P=0.002) and ESR1 wild-type patients (HR=0.49; P<0.001).

The authors concluded that plasma analysis for ESR1 mutations after progression on prior AI therapy may help direct choice of further endocrine-based therapy. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer. Fribbens C, O’Leary B, Kilburn L, et al. J Clin Oncol. 2016;34:2961-2968

XARELTO® for Heparin Induced Thrombocytopenia

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Heparin Induced Thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies to complexes of Platelet Factor 4 (PF4), a protein present in the platelet alpha granules and heparin and the incidence of HIT varies from 3-5% in patients treated with unfractionated heparin. The frequency of thromboemboli in HIT patients is 30-50% and women diagnosed with HIT are at a 1.7 times greater risk for thrombotic manifestations than men.

There are two types of HIT. Type 1 HIT is a non-immune disorder that results from the direct effect of heparin on platelet activation and manifests within the first 2 days after heparin exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 2 HIT however is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and can result in life threatening thrombotic complications. Patients with HIT more often experience thrombotic events such as Deep Venous Thrombosis, Pulmonary Embolism and sometimes Arterial thrombosis rather than bleeding episodes. The 4 T’s that raise clinical suspicion for HIT include Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and ruling out oTher causes of thrombocytopenia. Once a diagnosis of HIT is established, all heparin products should be stopped and alternative anticoagulants should be considered such as ARGATROBAN®, REFLUDAN® (Lepirudin), ANGIOMAXreg; (Bivalirudin) and ARIXTRA® (Fondaparinux). Warfarin may cause microthrombosis in patients with HIT and should be avoided and should be started only after the platelet count exceeds 150 x 109/L. IVC filters should be avoided as well.

The currently approved therapies for the treatment of HIT however are parenteral preparations and require laboratory coagulation monitoring. XARELTO® is a direct oral anti-Xa inhibitor and is presently approved by the FDA for the prevention and treatment of Deep Vein Thrombosis and Pulmonary Embolism as well as prevention of thromboembolic events in patients with Atrial Fibrillation. XARELTO® could be an ideal agent for patients with HIT, as it can be administered orally at a fixed dose and does not require routine coagulation monitoring.

The purpose of this study was to determine the safety and efficacy of XARELTO® in patients suspected or confirmed to have HIT. The authors in this multicenter, single-arm, prospective cohort study, reviewed the data of 22 consecutive adults with suspected or confirmed HIT. Patients received XARELTO® 15 mg PO BID until a local HIT assay result was available. Patients with a positive local assay result continued XARELTO® 15 mg PO BID until platelet recovery (or until day 21 if they had acute thrombosis at the time of entry into the study). The dose of XARELTO® was then changed to 20 mg PO daily, until day 30. This study was slated to enroll 200 patients but the study was terminated early after 22 patients were enrolled, because of difficulty in recruitment.

It was noted that the incidence of new, symptomatic, objectively confirmed, venous or arterial thromboembolism at 30 days in the HIT positive group (Primary endpoint), was 4.5% and one HIT-positive patient required limb amputation despite platelet recovery. Nine out of 10 HIT-positive patients with thrombocytopenia had platelet recovery.

It was concluded that based on this small study, XARELTO® was effective for treating patients with confirmed HIT, and also facilitated platelet recovery. This first prospective study of XARELTO® in HIT patients has a limited number of patients and the 22 patients in this study were enrolled over a 2.5 year period, which demonstrated the difficulty in enrolling patients in this study. Nonetheless, it is unlikely that larger studies will be designed to compare XARELTO® to one of the parenteral preparations. Based on the available data, XARELTO® may fulfill an unmet need for the management of patients with Heparin Induced Thrombocytopenia. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. Linkins LA, Warkentin TE, Pai M, et al. J Thromb Haemost 2016;14:1206-1210.

First Line KEYTRUDA® Superior to Chemotherapy in Advanced NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers. The FDA in October, 2016 approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have high PD-L1 expression (Tumor Proportion Score greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized, phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for 35 cycles or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety.

The median PFS was 10.3 months in the KEYTRUDA® group versus 6.0 months in the chemotherapy group (HR=0.50; P<0.001). This benefit was observed across all patient subgroups including tumor histologic type and chemotherapy regimen administered. The estimated Overall Survival at 6 months was 80.2% in the KEYTRUDA® group versus 72.4% in the chemotherapy group (HR=0.60; P=0.005). Patients in the KEYTRUDA® group experienced higher Response Rates than in the chemotherapy group (44.8% vs. 27.8%) as well as longer median duration of response (Not Reached versus 6.3 months). These benefits were realized even after 43.7% of the patients in the chemotherapy group following progression, had crossed over to receive KEYTRUDA®. Adverse events of any grade were less frequent in the KEYTRUDA® group compared to the chemotherapy group, with diarrhea, fatigue and pyrexia being more common in the KEYTRUDA® group whereas anemia, nausea and fatigue were more often noted in the chemotherapy group. As expected, immune-mediated adverse events (including pneumonitis) occurred more frequently with KEYTRUDA® whereas cytopenias occurred more frequently with chemotherapy.

It was concluded that in treatment naïve patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater, KEYTRUDA® was associated with significantly longer Progression Free and Overall Survival and with fewer adverse events, compared with platinum-based chemotherapy. This landmark trial is practice changing for advanced NSCLC. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. Reck M, Rodríguez-Abreu D, Robinson AG, et al. for the KEYNOTE-024 Investigators. October 9, 2016DOI: 10.1056/NEJMoa1606774

Bone Metastases – ZOMETA® every 12 Weeks Non-Inferior to Every 4 Weeks Schedule

SUMMARY: Bones are the third most common site of metastatic disease and approximately 100,000 cases of bone metastasis are reported in the United States each year. Cancers originating in the breast, prostate, lung, thyroid and kidney, are more likely to metastasize to the bone. Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with bone metastases. Bisphosphonates can also reduce bone pain and may improve Quality of life. Intravenous bisphosphonates, Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the US for the treatment of bone metastases. ZOMETA®, a third generation amino-bisphosphonate, has however largely replaced AREDIA® because of its superior efficacy, reducing pain and the incidence of Skeletal Related Events, by 25% to 40%. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks, following diagnoses of bone metastases. However, the optimal treatment schedule has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential toxicities and the incidence of these toxicities increase with cumulative drug exposure.

The purpose of this study was to determine whether ZOMETA® administered every 12 weeks was non-inferior to ZOMETA® administered every 4 weeks. In this open-label, non-inferiority trial, 1822 patients were enrolled (Breast,N=855, Prostate,N=689 and Myeloma,N=278), and were randomly assigned in a 1:1 ratio to receive ZOMETA® every 4 weeks or every 12 weeks, for 2 years. The median age was 65 yrs and patients had at least one site of bone involvement. The Primary endpoint was incidence of at least one Skeletal Related Event within 2 years (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) after randomization. Secondary endpoints included skeletal morbidity rates (mean number of Skeletal Related Events per year), performance status, pain using the Brief Pain Inventory and incidences of ONJ and renal dysfunction. Both treatment groups were well matched. Patients in this trial were stratified by disease and analyses by disease, was pre-planned.

In the 795 patients who completed the study at 2 years, 29.5% of patients receiving ZOMETA® every 4 weeks and 28.6% of patients receiving ZOMETA® every 12 weeks experienced at least 1 Skeletal Related Event and this was not significantly different. With regards to Secondary endpoints, there were still no significant differences between the two treatment groups with regards to Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction.

The authors concluded that ZOMETA® administered every 3 months for 2 years is non-inferior to ZOMETA®administered every 4 weeks for 2 years, among patients with breast cancer, prostate cancer and multiple myeloma, with bone metastases. A less frequent dosing of ZOMETA® compared with the standard monthly dosing, may also be more convenient for the patients and cost effective. XGEVA®, a RANK ligand (RANKL) inhibitor is also approved in the US for the treatment of bone metastases from solid tumors. A study is underway comparing XGEVA® administered every 4 weeks to every 12 weeks, in patients with metastatic breast and prostate cancer. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases. A Randomized Clinical Trial. Himelstein AL, Foster JC, Khatcheressian JL, et al. JAMA. 2017;317:48-58

A New Treatment Algorithm for the Upfront Treatment of Chronic Lymphocytic Leukemia

SUMMARY: The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) were diagnosed in 2016 and approximately 4660 patients died from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. A new treatment algorithm for the upfront treatment of CLL divides treatment naïve CLL patients into three groups and therapy should be chosen accordingly:

GROUP 1 consists of elderly patients with comorbidities who are unfit for aggressive interventions. The goal of therapy for this patient group should be to minimize toxicity rather than achieve long term remissions. In elderly CLL patients with comorbid conditions, Chlorambucil was often considered as a standard first-line therapy because of the higher rate of toxicities associated with FLUDARA® (Fludarabine) and TREANDA® (Bendamustine). The preferred choice for this group now is IMBRUVICA® (Ibrutinib). IMBRUVICA® is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling.

In CLL patients 65 years or older with relapsed or refractory disease (94%), or who were treatment-naive (85%), long term treatment and follow up with single-agent IMBRUVICA® resulted in high response rates across all subgroups of patients. It was noted that there has been increasing Complete Response Rate with each follow up in the treatment naïve group with a Complete Response Rate of 26%. (2015 AACR Annual Meeting. Abstract CT132). Of the 94 patients treated with IMBRUVICA®, at 45 months of follow up, the Progression Free Survival (PFS) at 30 months was 96% and Overall Survival (OS) rate was 96% in treatment-naive group, whereas the 30 month PFS was 76% and OS rate was 87% in relapsed/refractory patient group. The median PFS in patients with del(17p) was 32.4 month compared to 12 months with previously published best front line therapies.

In the RESONATE trial, which compared IMBRUVICA® to ARZERRA® (Ofatumumab) in patients with relapsed/refractory CLL (N Engl J Med 371:213-223, 2014), median PFS was not reached with IMBRUVICA® compared to a median PFS of 8.1 months with ARZERRA®, representing a 78% reduction in the risk of progression (HR=0.22; P<0.001). IMBRUVICA® also significantly improved Overall Survival (HR=0.43; P=0.005). The Overall Response Rate was also significantly higher in the IMBRUVICA® group than in the ARZERRA® group (42.6% versus 4.1%; P<0.001). Toxicities with IMBUVICA® are mild and include diarrhea and ecchymoses. Atrial fibrillation is seen in approximately 8% of elderly patients and needs attention.

GROUP 2 includes young fit patients with IGVH mutations for whom more aggressive combination therapy should be recommended for long term benefit. This group of patients should be offered three drug regimen consisting of FCR – FLUDARA®/Cyclophosphamide/RITUXAN® (Rituximab). The long term follow up of the pivotal FCR300 study revealed that 40% of patients were progression free at 14 years with a plateau noted in the PFS curve (Blood 127:303-309, 2016). About 60% of the patients with the IGVH mutation who were negative for Minimal Residual Disease (MRD) at the end of treatment, were progression free at 14 years. It was also demonstrated in a subsequent cohort that testing negative for Minimal Residual Disease after a response to FCR regimen was the most important determinant of Progression Free and Overall Survival. Among responders to FCR who were MRD negative, there was only one progression and no deaths after 4 years. Patients with IGVH-mutated disease had a 2.7-fold higher chance of being MRD negative after treatment with FCR. Bendamustine/RITUXAN® regimen is also often recommended for young and fit patients with Chronic Lymphocytic Leukemia, as the risk of neutropenia and infections are lower. However, FCR is associated with longer remissions by at least one year compared to Bendamustine/RITUXAN®.

GROUP 3 comprises of fit patients who are IGVH mutation-negative and will not achieve long remissions with combination chemotherapy. FCR regimen will not achieve 10-15 year remissions in this patient group and these patients should either be treated with IMBRUVICA® or enrolled in clinical trials.

ZYDELIG® (Idelalisib) is a highly selective oral inhibitor of the enzyme phosphoinositide 3-kinase (PI3K) and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. In the pivotal trial of previously treated patients with recurrent CLL (N Engl J Med 370:997-1007, 2014), the median PFS for the RITUXAN®/ ZYDELIG® combination group has not yet been reached, whereas the median PFS for the RITUXAN®/placebo arm was 5.5 months (HR=0.15; P<0.0001). This suggested an 85% reduction in the risk of progression. Further, the PFS was favorable in the poor prognosis patients with either a 17p deletion or p53 mutation, when ZYDELIG® was combined with RITUXAN® (HR=0.12). An improvement in the Overall Survival (OS) was also noted in the ZYDELIG® group compared with patients in the RITUXAN® alone group (HR=0.28; P=0.018). The combination of ZYDELIG® and RITUXAN® had an Overall Response Rate of 81% compared with 13% in the RITUXAN® alone group (P<0 .0001). Patients treated with a combination of ZYDELIG® and RITUXAN® also had a higher decrease in lymphadenopathy (93%) compared with 4% in the RITUXAN® alone group (P<0.0001). Lymphocytosis resolves more slowly with ZYDELIG® than with IMBRUVICA® and therefore, ZYDELIG® is combined with RITUXAN®. ZYDELIG® should not be used as first line therapy due to associated toxicities such as colitis, elevated transaminases and pneumonitis seen more so in treatment naïve patients, as these patients have less T-cell depletion.

Chronic Lymphocytic Leukemia with del(17p)

IMBRUVICA® is the preferred first line therapy. VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. In a pivotal study, VENCLEXTA® monotherapy in patients with Relapsed/Refractory del(17p) CLL resulted in a ORR of 79.4% with 8% Complete Responses and some patients attained MRD-negative status in their peripheral blood which is remarkable (N Engl J Med 374:311-322, 2016). The median Duration of Response (DoR) has not been reached. This drug should be considered as second line therapy.

Dr O’Brien concluded that this new evidence based treatment algorithm stratifies patients differently from the traditional algorithm. O’Brien SM: How do we sequence the best treatment options for patients with CLL based on age and prognostic features? 2016 Pan Pacific Lymphoma Conference. Presented July 22, 2016. Koloa, HI, United States

VISTOGARD® – An Antidote for 5-FU Overexposure

SUMMARY: VISTOGARD® (Uridine Triacetate) is presently approved in the US for the emergency treatment of adult and pediatric patients, who had severe or life-threatening toxicities within 4 days of treatment, following an overdose of 5-FluoroUracil (5-FU) or XELODA® (Capecitabine). Toxicities related to 5-FU or XELODA® can be caused by impaired drug clearance, Dihydropyrimidine Dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5-FU. Additionally, 5-FU overdoses resulting in death can occur because of infusion pump errors, dosage miscalculations and accidental or suicidal ingestion of XELODA®. These toxicities can manifest as severe mucositis, cytopenias, central neurotoxicity and acute cardiomyopathy.

VISTOGARD® is a pyrimidine analog and following oral administration is deacetylated by nonspecific esterases, yielding Uridine in the circulation. Uridine is a direct antagonist of 5-FU and competitively inhibits 5-FU from incorporating in normal tissues, thus reducing cell damage and cell death. The authors reported the efficacy of VISTOGARD® in two open-label clinical trials in which patients who presented with a 5-FU/XELODA® overdose (N=142) or patients with early onset of severe toxicities (N=26), were treated. These patients received VISTOGARD® granules 10 grams every 6 hours for 20 doses, starting within 96 hours after the termination of 5-FU/XELODA® therapy. The median age was 58 years. Because there were no antidotes available for 5-FU toxicity at the time of this study, and the use of a placebo was unethical, the outcomes of this study were compared to a historical cohort of patients gathered from all available literature (control group), who overdosed on 5-FU and received only best supportive care. The primary endpoint of these studies was survival at 30 days or until chemotherapy could resume, if prior to 30 days.

Of the 142 overdose patients treated with VISTOGARD®,137 patients (96%) survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity and additionally, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical control cohort, 21 of 25 patients (84%) died. Among the 141 VISTOGARD® treated overdose patients with a diagnosis of cancer, 53 resumed chemotherapy in less than 30 days (median time after 5-FU of 19.6 days), indicating a rapid recovery from toxicity. The most common toxicities in patients receiving VISTOGARD® included, nausea, vomiting and diarrhea.

The authors concluded that VISTOGARD® is a safe and effective antidote for 5-FU overexposure, and can facilitate rapid recovery and resumption of chemotherapy. Patients should take VISTOGARD® as soon as possible after overdose, regardless of symptoms or within 4 days of severe or life threatening toxicity. It should be noted that VISTOGARD® is not recommended for treatment of non-emergency adverse events associated with 5-FU and XELODA®, as this therapy may significantly decrease the efficacy of these chemotherapy agents. Emergency use of uridine triacetate for the prevention and treatment of life-threatening 5-fluorouracil and capecitabine toxicity. Ma WW, Saif WM, El-Rayes BF, et al. Cancer 2017;123:345-356.

Late Breaking Abstract – ASCO 2016 ROVA-T, First Targeted Treatment for Small Cell lung Cancer

SUMMARY: Lung cancer is the second most common cancer in both men and women and the American Cancer Society estimates that for 2016, about 224,390 new cases of lung cancer will be diagnosed and over 158,000 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small cell lung cancer (SCLC) accounts for approximately 13-15 percent of all lung cancers and is aggressive. The five year survival rate for extensive stage SCLC is less than 5% with a median survival of 9 to 10 months from the time of diagnosis. Patients are often treated with chemotherapy and radiation in the first and second line setting. The Overall Response Rate (ORR) in the third line setting is approximately 18% and the one year Overall Survival is approximately 12%. These patients typically have a poor prognosis with limited treatment options. Delta-like protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 80% of the tumors).

Rovalpituzumab Tesirine (Rova-T) is a first-in-class DLL3-targeted Antibody-Drug Conjugate (ADC) comprised of a humanized anti-DLL3 monoclonal antibody, conjugated to a DNA-damaging PyrroloBenzoDiazepine (PBD) dimer toxin. Rova-T delivers the cytotoxin directly to the DLL3-expressing cancer cells while minimizing toxicity to healthy cells.

The authors in this open-label, Phase 1a/1b, multicenter study, included seventy four (N=74) patients with SCLC who had progressed after at least one previous systemic therapy. Previous therapies included Platinum/Etoposide (96%) and radiation therapy (82%). The majority of patients (76%) had extensive disease at presentation, with 28% having CNS metastases. Over 85% of patients had DLL3 expression on 1% or more of tumor cells and 67% of the patients had DLL3 expression on 50% or more of tumor cells (DLL3-high expression). Patients received Rova-T at doses ranging from 0.05 to 0.8 mg/kg every 3 or 6 weeks. The median age was 61 years. The primary endpoints of the study were Overall Response Rate (ORR) and Maximum Tolerated Dose and secondary endpoints included Overall Survival (OS) and Progression Free Survival (PFS).

Rova-T demonstrated an Overall Response Rate of 39% and Clinical Benefit Rate (stable disease or better) of 89%, in patients with recurrent or refractory Small Cell Lung Cancer identified with high expression of DLL3. The one year Overall Survival rate was 32% in the patient group identified with high expression of DLL3. The most common adverse events were rash, fatigue, nausea, decreased appetite, pleural effusion, peripheral edema and thrombocytopenia.

The authors concluded that Rovalpituzumab Tesirine (Rova-T) has significant single-agent anti-tumor activity with manageable toxicity, in recurrent or refractory SCLC, and is the first biomarker-directed therapy to be defined, for the treatment of Small Cell Lung Cancer. Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC). Rudin CM, Pietanza MC, Bauer TM, et al. J Clin Oncol 34, 2016 (suppl; abstr LBA8505)

ASCO Guideline – Adjuvant Systemic Therapy Decision Making for Early Stage Operable Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their life time. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant therapy. The ASCO Clinical Practice Guidelines Committee endorsed a set of Cancer Care Ontario guideline recommendations that addressed the role of a range of patient and disease characteristics, in selecting adjuvant therapy for women with early-stage breast cancer. This guideline does not address the selection of optimal adjuvant chemotherapy regimens.

Guideline Question: Which patient and disease factors should be considered in selecting adjuvant therapy for women with early-stage breast cancer?

Target Population: Female patients who are being considered for, or who are receiving systemic therapy for early-stage invasive breast cancer (Stages I–IIA, T1N0–1, T2N0).


Decisions regarding adjuvant therapy should be based on relevant (either prognostic or predictive) information and consideration given to-

1) Lymph node status, T stage, Estrogen Receptor status, Progesterone Receptor status, HER2 status, tumor grade, and presence of tumor lymphovascular invasion.

2) Risk-stratification tools including Oncotype DX score (for hormone receptor-positive, N0 or N1mic or isolated tumor cell, and HER2-negative cancers) and Adjuvant! Online.

3) Patient age, menopausal status, and medical comorbidities.

For patients in whom chemotherapy would likely be tolerated and for whom chemotherapy is acceptable, adjuvant chemotherapy should be considered if the following characteristics are present:

1) Lymph node-positive tumor (at least one node with macrometastatic deposit > 2 mm)

2) Estrogen receptor-negative tumor (> 5 mm)

3) HER2-positive tumor

4) High-risk node-negative tumors (> 5 mm) and another high-risk feature

5) Adjuvant! Online 10-year risk of death from breast cancer > 10%.

Patients with node-negative early stage breast cancer with high risk features who should be considered candidates for chemotherapy include

1) Tumors > 5 mm

2) Grade III histology

3) Triple negative tumors

4) Lymphovascular invasion

5) Oncotype DX recurrence score associated with an estimated distant relapse risk ≥ 15% at 10 years

6) HER2-positive tumors

(The ASCO panel suggested an estimated distant relapse risk > 20% in this setting).

Patients with tumor size < 5 mm, node-negative tumors, and no other high-risk features, may not benefit from adjuvant chemotherapy.

Adjuvant chemotherapy may not be required in patients with HER2-negative, strongly ER-positive, and PR-positive breast cancer and any of the following additional characteristics: positive nodes with micrometastasis only (< 2 mm), or Tumor size < 5 mm, or Oncotype DX recurrence score with an estimated distant relapse risk < 15% at 10 years. (The ASCO panel suggested an estimated distant relapse risk < 10% at 10 years in this setting)

ASCO Panel Discussion Points

Areas that warrant further consideration include-

1) Tumor histology and adjuvant therapy recommendations

2) Risk-stratification tools and proposed Oncotype DX recurrence score thresholds to guide decisions about chemotherapy

3) Patient factors in decision-making.

The panel noted that some uncommon breast cancer subtypes (eg, tubular, mucinous) may have a favorable prognosis and that such histologic information may be relevant for making decisions regarding adjuvant chemotherapy. Additionally, factors such as Grade III disease and lymphovascular invasion generally should not be used in isolation in decision-making but considered within the overall clinical context.

Role of patient and disease factors in adjuvant systemic therapy decision making for early-stage, operable breast cancer: Henry NL, Somerfield MR, Abramson VG, et al. American Society of Clinical Oncology endorsement of Cancer Care Ontario guideline recommendations. J Clin Oncol 34:2303-2311, 2016